AT, COMPLEMENTATION GROUP C, INCLUDED
ATA, INCLUDED
AT, COMPLEMENTATION GROUP D, INCLUDED
ATAXIA-TELANGIECTASIA VARIANT, INCLUDED
AT, COMPLEMENTATION GROUP E, INCLUDED
ATC, INCLUDED
ATD, INCLUDED
ATE, INCLUDED
LOUIS-BAR SYNDROME AT, COMPLEMENTATION GROUP A, INCLUDED
AT
AT1
Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant ... Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait has been used to identify complementation groups for the classic form of the disease (Jaspers et al., 1988). At least 4 of these (A, C, D, and E) map to chromosome 11q23 (Sanal et al., 1990) and are associated with mutations in the ATM gene.
Patients present in early childhood with progressive cerebellar ataxia and later develop conjunctival telangiectases, other progressive neurologic degeneration, sinopulmonary infection, and malignancies. Telangiectases typically develop between 3 and 5 years of age. The earlier ... - Homozygotes Patients present in early childhood with progressive cerebellar ataxia and later develop conjunctival telangiectases, other progressive neurologic degeneration, sinopulmonary infection, and malignancies. Telangiectases typically develop between 3 and 5 years of age. The earlier ataxia can be misdiagnosed as ataxic cerebral palsy before the appearance of oculocutaneous telangiectases. Gatti et al. (1991) contended that oculocutaneous telangiectases eventually occur in all patients, while Maserati et al. (1988) wrote that patients without telangiectases are not uncommon. A characteristic oculomotor apraxia, i.e., difficulty in the initiation of voluntary eye movements, frequently precedes the development of telangiectases. Gonadal dysfunction in ataxia-telangiectasia was discussed by Miller and Chatten (1967), Zadik et al. (1978), and others. Thibaut et al. (1994) reviewed cases of necrobiosis lipoidica in association with ataxia-telangiectasia. According to Boder (1985), the oldest known AT patients were a man who died in November 1978 at age 52 years and his sister who died in July 1979 at the age of almost 49 years. The sister was the subject of the report by Saxon et al. (1979) on T-cell leukemia in AT. The possibility of heteroalleles at the ataxia-telangiectasia loci might be suggested. - Neurologic Manifestations AT may be the most common syndromic progressive cerebellar ataxia of early childhood. Truncal ataxia precedes appendicular ataxia. Oculomotor apraxia is progressive and opticokinetic nystagmus is absent. Choreoathetosis and/or dystonia occur in 90% of patients and can be severe. Deep tendon reflexes become diminished or absent by age 8 and patients later develop diminished large-fiber sensation. Gatti et al. (1991) pointed out that 'a significant proportion of older patients in their twenties and early thirties develop progressive spinal muscular atrophy, affecting mostly hands and feet, and dystonia.' Interosseous muscular atrophy in the hands in combination with the early-onset dystonic posturing leads to striking combined flexion-extension contractures of the fingers, which they illustrated. Mental retardation is not a feature of AT, although some older patients have a severe loss of short-term memory. Neurologic dysfunction is a clinically invariable feature in homozygotes. Woods and Taylor (1992) studied 70 affected persons in the British Isles, 29 females and 41 males with an age range of 2 to 42 years. Most presented by 3 years of age with truncal ataxia. All had ataxia, ocular motor apraxia, an impassive face, and dysarthria, although clinical immune deficiency was present only in 43 of 70 patients. Ocular telangiectases was seen in all but one. All 60 tested showed increased sensitivity to ionizing radiation, 43 of 48 had an elevated alpha-fetoprotein level, and 14 of 21 had an immunoglobulin deficiency. - Malignancy Patients with AT have a strong predisposition to malignancy. Hecht et al. (1966) observed lymphocytic leukemia in patients with AT. A nonleukemic sib and 2 unrelated patients with AT had multiple chromosomal breaks and impaired responsiveness to phytohemagglutinin. This was the first report of chromosomal breakage in AT. Leukemia and chromosomal abnormalities occur in at least 2 other mendelian disorders--Fanconi pancytopenia (FA; 227650) and Bloom syndrome (BS; 210900). Saxon et al. (1979) demonstrated thymic origin of the neoplastic cells in a 48-year-old woman with AT and chronic lymphatic leukemia. The neoplastic cells had the specific 14q+ translocation and showed both helper and suppressor function, suggesting that the malignant transformation had occurred in an uncommitted T-lymphocyte precursor that was capable of differentiation. This is a situation comparable to chronic myeloid leukemia in which the Philadelphia chromosome occurs in a stem cell progenitor of both polymorphs and megakaryocytes. In general, lymphomas in AT patients tend to be of B-cell origin (B-CLL), whereas the leukemias tend to be of the T-CLL type. Rosen and Harris (1987) discussed the case of a 30-year-old man with AT who developed a malignant lymphoma of B-cell type involving the tonsil and lungs. Haerer et al. (1969) described a black sibship of 12, of whom 5 had ataxia-telangiectasia; 2 of those affected died of mucinous adenocarcinoma of the stomach at ages 21 and 19 years. Bigbee et al. (1989) demonstrated an increased frequency of somatic cell mutation in vivo in individuals with AT. Obligate heterozygotes for the disease did not appear to have a significantly increased frequency of such mutations. The authors speculated that the predisposition to somatic cell mutation may be related to the increased susceptibility to cancer in AT homozygotes. Other solid tumors, including medulloblastomas and gliomas, occur with increased frequency in AT (Gatti et al., 1991). - Immune Disorders Defects of the immune mechanism and hypoplasia of the thymus have been demonstrated. Serum IgG2 or IgA levels are diminished or absent in 80% and 60% of patients, respectively (Gatti et al., 1991). IgE levels can be diminished, IgM levels diminished or normal. Peripheral lymphopenia as well as decreased cellular immunity to intradermally injected test antigens can be seen early in the disorder. Sinopulmonary infections are frequent, but their severity cannot be simply correlated with the degree of immunodeficiency. Carbonari et al. (1990) found that patients with AT have more circulating T cells bearing gamma/delta receptors characteristic of immature cells than alpha/beta receptors typical of mature cells. Normal ratios were found in the patients with other immune deficits, except for 1 child with a primary T-cell defect. Peterson and Funkhouser (1990) proposed that these findings are consistent with a defect in genetic recombination leading to the switch from gamma/delta to alpha/beta. There may also be a defect in DNA ligation or some other aspect of DNA repair. Elucidation of the molecular abnormalities of lymphocytes may demonstrate fundamental molecular mechanisms for cellular differentiation not only of lymphocytes but of other cell systems such as the nervous system. - Variant Ataxia-Telangiectasia (Atypical) Ying and Decoteau (1981) described a family in which a brother and sister may have had an allelic (and milder) form of AT. The proband, a 58-year-old male of Saskatchewan Mennonite origin, had spinocerebellar degeneration associated with choreiform movements beginning at about age 10 years. Despite considerable physical handicap, he was able to work as a delivery man in the family store. No telangiectases were found at age 44 (they were carefully sought because of typical AT in a niece) or on later examinations. He showed total absence of IgA in serum and concentrated saliva and low IgE in serum. He was anergic on skin testing. Glucose tolerance was markedly decreased. Serum alpha-fetoprotein was 840 ng per ml (normal, less than 10 ng per ml). Lymphocyte response to phytohemagglutinin was blunted. He died of lymphoma at age 58. He showed cytogenetic abnormalities typical of AT; 4 abnormal clones were identified, all involving chromosome 14 in some way. The proband had 4 brothers and 2 sisters. A brother died of leukemia at age 16. A sister was likewise diagnosed as having spinocerebellar degeneration with choreiform movements at age 46; she died at age 55 of breast cancer. The proband's niece with typical AT had telangiectases of the bulbar conjunctivae and earlobes noted at age 3, when she began to have recurrent and severe sinopulmonary infections. She died at age 20 of staphylococcal pneumonia superimposed on bronchiectasis. The brother and sister who died in their 50s may have been genetic compounds. Their parents denied consanguinity. Taylor et al. (1987) described 3 patients who were atypical in terms of clinical features and cellular features as observed in vitro. One of the patients was a 45-year-old woman with onset of neurologic manifestations in her early twenties. Maserati et al. (1988) described 2 sisters, aged 9 and 11 years, with a progressive neurologic disorder similar to AT, chromosome instability with rearrangements involving chromosomes 7 and 14, but no telangiectases or immunologic anomalies typical of AT. Byrne et al. (1984) reported similar cases of ataxia without telangiectases with selective IgE deficiency but normal IgA and alpha-fetoprotein. Ziv et al. (1989) described 2 Turkish sibs with an atypically prolonged course and atypical behavior of cultured fibroblasts. See 208910 and 208920 for AT-like syndromes. Rare cases of AT patients with milder manifestations of the clinical or cellular characteristics of the disease have been reported and have been designated 'AT variants.' Gilad et al. (1998) quantified ATM protein levels in 6 patients with an AT variant and searched their ATM genes for mutations. Cell lines from these patients exhibited considerable variability in radiosensitivity while showing the typical radioresistant DNA synthesis of AT cells. Unlike classic AT patients, however, these patients exhibited 1 to 17% of the normal level of ATM. The underlying genotypes were either homozygous for mutations expected to produce mild phenotypes or compound heterozygous for a mild and a severe mutation. In an attempt to determine whether the AT(Fresno) variation correlated with ATM mutations and levels of ATM protein expression, Gilad et al. (1998) searched for ATM mutations in a cell line derived from one of the sisters studied by Curry et al. (1989). This cell line was found to be devoid of the ATM protein and homozygous for a severe ATM mutation. Gilad et al. (1998) concluded that certain AT variant phenotypes, including some of those without telangiectasia, represent ATM mutations. Saviozzi et al. (2002) noted that milder cases of AT, termed 'AT variants,' comprise a heterogeneous group characterized by later onset of clinical symptoms, slower progression, extended life span compared to most AT patients, and decreased levels of chromosomal instability and cellular radiosensitivity. In these patients, telangiectasia and/or immunodeficiency may be absent, while the neurologic features are present. The genotype of AT variants is most often compound heterozygous for a severe mutation together with a mild or leaky mutation, which expresses some ATM protein with residual function. In 2 sisters with variant AT with onset of ataxia at 27 years, polyneuropathy, choreoathetosis, and absence of telangiectasia, immunodeficiency, and cancer, Saviozzi et al. (2002) identified compound heterozygosity in the ATM gene for a missense (607585.0028) and a frameshift (607585.0029) mutation. Western blot analysis showed a low level of ATM protein with residual phosphorylation activity, which the authors suggested contributed to the milder phenotype. Hiel et al. (2006) reported 3 brothers and an unrelated woman with late-onset AT. All 4 were ambulatory and ranged in age from 37 to 43 years; unsteady gait developed approximately 10 years earlier. Cerebellar signs were mild, but all had striking distal muscular atrophy and weakness, decreased or absent ankle reflexes, and normal or borderline delayed motor conduction velocities with markedly decreased compound muscle action potentials. Muscle biopsies showed neurogenic changes. The patients had normal sensation and normal sensory studies. Other features included severe resting tremor, slight intention tremor, and mild dysarthria. ATM phosphorylation activity was only slightly decreased, suggesting that other factors were involved in damage to anterior horn neurons. Verhagen et al. (2009) provided a retrospective analysis of 13 adult patients with variant AT from 9 families and 6 unrelated patients with classic AT. All patients were from the Netherlands; 2 of the patients with variant AT had been reported by Hiel et al. (2006). All patients with classic AT were diagnosed in childhood, presented with ataxic gait, and were wheelchair-bound by age 11 years. Five of the 6 died between ages 21 and 27. Those with variant AT were only correctly diagnosed in adulthood, although 7 presented with slowly progressive chorea-athetosis from early childhood. Five with variant AT presented with resting tremor between age 12 to 34, and the remaining patient with variant AT presented with distal muscle weakness of the lower extremities at age 6. Five patients with variant AT became wheelchair-bound between ages 15 and 43, and 2 had died of malignancy at ages 51 and 23 years, respectively. All variant AT patients had dysarthria by adulthood, 9 had choreoathetosis, 8 had resting tremor, 7 had oculomotor apraxia, and 5 had nystagmus. Eight patients had normal cerebellum on MRI, whereas 4 had cerebellar atrophy. Only 7 of 13 had ocular telangiectasia, but all had increased serum alpha-fetoprotein. Six with variant AT had polyneuropathy. Four developed a malignancy, including ALL, pituitary tumor, and breast cancer. Only 1 had slightly decreased IgG levels. Chromosomal instability was found in 8 variant AT patients tested. Those with the mildest form of the disorder had residual ATM protein expression with kinase activity. Saunders-Pullman et al. (2012) reported 13 patients from 3 Canadian Mennonite families with variant AT due to a homozygous missense mutation in the ATM gene (A2067D; 607585.0033). The patients had onset of dystonia in the first 2 decades (range, 1-20 years). Dystonia mostly affected the neck, face, tongue, and limbs, and became generalized in 60% of patients. Dysarthria was very common. Additional features in some patients included myoclonus, facial choreiform movements, and irregular tremor. Some patients had clumsy gait, and although none had overt ataxia, 2 patients had ataxia in childhood that spontaneously resolved. None had prominent telangiectases. Postmortem examination showed mild loss of cerebellar Purkinje cells in 1 patient, but cerebellar atrophy was not a prominent finding in any of the patients. Cells from 2 mutation carriers showed increased radiosensitivity and only trace amounts of ATM protein. Heterozygous mutation carriers did not have dystonia. Family history revealed that 2 homozygous mutation carriers in 1 family had died of malignancy in adulthood. - Cancer Risk in Heterozygotes Welshimer and Swift (1982) studied families of homozygotes for AT, Fanconi anemia (FA), and xeroderma pigmentosum (XP; see 278700) to test the hypothesis that heterozygotes may be predisposed to some of the same congenital malformations and developmental disabilities that are common among homozygotes. Among XP relatives, 11 of 1,100 had unexplained mental retardation, whereas only 3 of 1,439 relatives of FA and AT homozygotes showed mental retardation. Four XP relatives but no FA or AT relatives had microcephaly. Idiopathic scoliosis and vertebral anomalies occurred in excess in AT relatives, while genitourinary and distal limb malformations were found in FA families. Swift (1980) defended, from the viewpoint of not causing anxiety, the usefulness and safety of cancer risk counseling of heterozygotes for AT. Swift et al. (1987) examined the cancer risk of heterozygotes for AT in 128 families, including 4 of Amish ancestry, 110 white non-Amish families, and 14 black families. They measured documented cancer incidence rather than cancer mortality based solely on death certificates and compared the cancer incidence in adult blood relatives of probands directly with that in spouse controls. The incidence rates in AT relatives were significantly elevated over those in spouse controls. In persons heterozygous for AT, the relative risk of cancer was estimated to be 2.3 for men and 3.1 for women. Breast cancer in women was the cancer most clearly associated with heterozygosity for AT. Swift et al. (1987) estimated that 8 to 18% of patients with breast cancer in the U.S. white population would be heterozygous for AT. Pippard et al. (1988) reported an excess of breast cancer deaths in British mothers of AT patients (significant at the 5% level), but no excess mortality from malignant neoplasms in the grandparents. Morrell et al. (1990) reported cancer incidence measured retrospectively in 574 close blood relatives of AT patients and 213 spouse controls in 44 previously unreported families. For heterozygous carriers of the AT gene, the relative risk of cancer was estimated to be 6.1 as compared with non-heterozygotes. The most frequent cancer site in the blood relatives was the female breast, with 9 cancers observed. Gatti et al. (1991) provided a review in which they noted the possibly high frequency of breast cancer in AT heterozygotes. Swift et al. (1991) reported the results of a prospective study of 1,599 adult blood relatives of patients with AT and 821 of their spouses distributed in 161 families. Cancer rates were significantly higher among the blood relatives than in their spouses, specifically in the subgroup of 294 blood relatives who were known to be heterozygous for the AT gene. The estimated risk of cancer of all types among heterozygotes as compared with noncarriers was 3.8 in men and 3.5 in women, and that for breast cancer in carrier women was 5.1. Among the blood relatives, women with breast cancer were more likely to have been exposed to selected sources of ionizing radiation than controls without cancer. Male and female blood relatives also had 3-fold and 2.6-fold excess mortality from all causes, respectively, from the ages of 20 through 59 years. Swift et al. (1991) suggested that diagnostic or occupational exposure to ionizing radiation increases the risk of breast cancer in women heterozygous for AT. The work of Swift et al. (1991) on the frequency of breast cancer in AT was critiqued by numerous authors, including Bridges and Arlett (1992). Since the genes responsible for most cases of AT are located on 11q, Wooster et al. (1993) typed 5 DNA markers in the AT region in 16 breast cancer families. They found no evidence for linkage between breast cancer and these markers and concluded that the contribution of AT to familial breast cancer is likely to be minimal. Athma et al. (1996) determined the AT gene carrier status of 776 blood relatives in 99 AT families by tracing the ATM gene in each family through tightly linked flanking DNA markers. There were 33 women with breast cancer who could be genotyped; 25 of these were AT heterozygotes, compared to an expected 14.9. For 21 breast cancers with onset before age 60, the odds ratio was 2.9 and for 12 cases with onset at age 60 or older, the odds ratio was 6.4. Thus, the breast cancer risk for AT heterozygous women is not limited to young women but appeared to be even higher at older ages. Athma et al. (1996) estimated that, of all breast cancers in the U.S., 6.6% may occur in women who are AT heterozygotes. This proportion is several times greater than the estimated proportion of carriers of BRCA1 mutations (113705) in breast cancer cases with onset at any age. The reported increased risk for breast cancer for AT family members has been most evident among younger women, leading to an age-specific relative risk model predicting that 8% of breast cancer in women under age 40 arises in AT carriers, compared with 2% of cases between 40 and 59 years (Easton, 1994). To test this hypothesis, FitzGerald et al. (1997) undertook a germline mutational analysis of the ATM gene in a population of women with early onset of breast cancer, using a protein truncation (PTT) assay to detect chain-terminating mutations, which account for 90% of mutations identified in children with AT. They detected a heterozygous ATM mutation in 2 of 202 (1%) controls, consistent with the frequency of AT carriers predicted from epidemiologic studies. ATM mutations were present in only 2 of 401 (0.5%) women with early onset of breast cancer (P = 0.6). FitzGerald et al. (1997) concluded that heterozygous ATM mutations do not confer genetic predisposition to early onset of breast cancer. The results of FitzGerald et al. (1997) are discrepant with those of Athma et al. (1996), who conducted a study 'from the other direction' by following identified AT mutations through the families of those with clinically recognized AT. Analysis of DNA markers flanking the AT gene allowed them to identify precisely which female relatives with breast cancer carried the AT mutation. On the basis of the genetic relationship between each case and the AT proband, the a priori probability that these 2 share the AT mutation was calculated. This led to an estimated relative risk of 3.8 as compared to noncarriers. This result was similar to that found by Easton (1994), who reanalyzed the previous studies of breast cancer risk in mothers (and other close relatives) of AT cases. Bishop and Hopper (1997) analyzed these 2 studies and suggested that they may not be discrepant. Indeed, they estimated that the study of FitzGerald et al. (1997) yielded an upper limit of the 95% confidence interval for the proportion of early onset breast cancer occurring in AT heterozygotes as 2.4% (assuming that their assay identified 75% of all mutations). In a family with multiple cancers, Bay et al. (1999) described heterozygosity for a mutant allele of ATM that caused skipping of exon 61 in the mRNA (607585.0020) and was associated with a previously undescribed polymorphism in intron 61. The mutation was inherited by 2 sisters, one of whom developed breast cancer at age 39 years and the second at age 44 years, from their mother, who developed kidney cancer at age 67 years. Studies of irradiated lymphocytes from both sisters revealed elevated numbers of chromatid breaks, typical of AT heterozygotes. In the breast tumor of the older sister, loss of heterozygosity (LOH) was found in the ATM region of 11q23.1, indicating that the normal ATM allele was lost in the breast tumor. LOH was not seen at the BRCA1 (113705) or BRCA2 (600185) loci. BRCA2 was considered an unlikely cancer-predisposing gene in this family because each sister inherited different chromosomes 13 from each parent. The findings suggested that haploinsufficiency at ATM may promote tumorigenesis, even though LOH at the ATM locus supported a more classic 2-hit tumor suppressor gene model. The finding that ATM heterozygotes have an increased relative risk for breast cancer had been supported by some studies but not confirmed by others. Broeks et al. (2000) analyzed germline mutations of the ATM gene in a group of Dutch patients with breast cancer using normal blood lymphocytes and the protein truncation test followed by genomic sequence analysis. A high percentage of ATM germline mutations was demonstrated among patients with sporadic breast cancer. The 82 patients included in this study had developed breast cancer before the age of 45 years and had survived 5 years or more (mean, 15 years), and in 33 (40%) of the patients a contralateral breast tumor had been diagnosed. Among these patients, 7 (8.5%) had germline mutations of the ATM gene, of which 5 were distinct. One splice site mutation, IVS10-6T-G (607585.0021), was detected 3 times in this series. Four heterozygous carriers had bilateral breast cancer. Broeks et al. (2000) concluded that ATM heterozygotes have an approximately 9-fold increased risk of developing a type of breast cancer characterized by frequent bilateral occurrence, early age at onset, and long-term survival. They suggested that the characteristics of this population of patients may explain why such a high frequency was found here and not in other series. Olsen et al. (2005) reported on an extended and enlarged follow-up study of cancer incidence in blood relatives of 75 patients with verified AT from 66 Nordic families. When 7 mothers of probands were excluded, no clear relationship was observed between the allocated mutation carrier probability of each family member and the extent of breast cancer risk. They concluded that the increased risk for female breast cancer seen in 66 Nordic AT families appeared to be restricted to women under the age of 55 years and was due mainly to a very high risk in the group of mothers. Olsen et al. (2005) concluded that the findings of breast cancer risk in mothers, but not in other likely mutation carriers, in this and other studies raised questions about the hypothesis of a simple causal relationship with ATM heterozygosity. Although the defining characteristic of recessive diseases is the absence of a phenotype in heterozygous carriers, Watts et al. (2002) suggested that expression profiling by microarray techniques might reveal subtle manifestations. Individual carriers of AT cannot be identified; as a group, however, carriers of a mutant AT allele have a phenotype that distinguishes them from normal control individuals: increased radiosensitivity and risk of cancer. Watts et al. (2002) showed that the phenotype was also detectable, in lymphoblastoid cells from AT carriers, as changes in expression level of many genes. The differences were manifested both in baseline expression levels and in response to ionizing radiation. The findings showed that carriers of the recessive disease may have an 'expression phenotype,' which suggested a new approach to the identification of carriers and enhanced understanding of their increased cancer risk. Renwick et al. (2006) screened individuals from 443 familial breast cancer pedigrees and 521 controls for ATM sequence variants and identified 12 mutations in affected individuals and 2 in controls (p = 0.0047). Their results demonstrated that ATM mutations that cause ataxia-telangiectasia in biallelic carriers are breast cancer susceptibility alleles in monoallelic carriers, with an estimated relative risk of 2.37 (95% CI = 1.57-3.78, p = 0.0003).
Savitsky et al. (1995) identified mutations in the ATM gene in ataxia-telangiectasia cases of complementation groups A, C, D, and E and in 4 other patients in whom the complementation group was not determined (see, e.g., 607585.0001). Thus ... Savitsky et al. (1995) identified mutations in the ATM gene in ataxia-telangiectasia cases of complementation groups A, C, D, and E and in 4 other patients in whom the complementation group was not determined (see, e.g., 607585.0001). Thus it appears that the complementation that is observed is intragenic and that all AT patients have mutations in a single gene. Concannon and Gatti (1997) discussed the genetic heterogeneity in AT and provided an update of mutations in the ATM gene. They noted that most AT patients from nonconsanguineous families were compound heterozygotes. Mutation detection at the ATM locus is difficult because of the large size of the gene (66 exons), the fact that mutations are located throughout the gene with no hotspots, and the difficulty of distinguishing mutations from polymorphisms. Buzin et al. (2003) used a method called DOVAM-S (Detection of Virtually All Mutations by SSCP), a robotically-enhanced, multiplexed scanning method that is a highly sensitive modification of SSCP. They studied 43 unrelated patients and 4 obligate carriers. The results of this complete scan showed that 86% of causative ATM mutations were truncating and 14% were missense. See MOLECULAR GENETICS section in 607585.
On the basis of a 'vigorous case finding' in the United States in 2 time periods, Swift et al. (1986) estimated the incidence and gene frequency of AT. The highest observed incidence was in the state of Michigan ... On the basis of a 'vigorous case finding' in the United States in 2 time periods, Swift et al. (1986) estimated the incidence and gene frequency of AT. The highest observed incidence was in the state of Michigan for the period 1965 to 1969 when white AT patients were born at the rate of 11.3 per million births. Based on the incidence data, the minimum frequency of a single hypothetical AT gene in the U.S. white population was estimated to be 0.0017. Pedigree analysis, which estimates the gene frequency from the proportion of affected close blood relatives of homozygous probands, estimated the most likely gene frequency to be 0.007 on the assumption that AT is a single homogeneous genetic syndrome. Given that complementation analysis has demonstrated genetic heterogeneity in AT, the AT heterozygote frequency might fall between 0.68% and 7.7%, with 2.8% being a likely estimate. In the West Midlands of England, the birth frequency of AT was estimated to be about 1 in 300,000. Stankovic et al. (1998) reported the spectrum of 59 ATM mutations observed in AT patients in the British Isles. Of the 51 ATM mutations identified in families native to the British Isles, 11 were founder mutations, and 2 of these 11 conferred a milder clinical phenotype with respect to both cerebellar degeneration and cellular features. In 2 AT families, a 7271T-G mutation of the ATM gene appeared to be associated with an increased risk of breast cancer in both homozygotes and heterozygotes, although there was a less severe AT phenotype in terms of the degree of cerebellar degeneration. This mutation was associated with expression of full-length ATM protein at a level comparable to that in unaffected individuals. In addition, Stankovic et al. (1998) studied 18 AT patients, in 15 families, who developed leukemia, lymphoma, preleukemic T-cell proliferation, or Hodgkin lymphoma, mostly in childhood. A wide variety of ATM mutation types, including missense mutations and in-frame deletions, were seen in this group of patients. The authors showed that 25% of all AT patients carried in-frame deletions or missense mutations, many of which were also associated with expression of mutant ATM protein. Ejima and Sasaki (1998) studied 8 unrelated Japanese families with ataxia-telangiectasia for mutations in the ATM gene. Six different mutations were found on 12 of the 16 alleles examined. Two mutations, 4612del165 (607585.0014) and 7883del5, were found more frequently than the others; 7 of 16 (44%) of the mutant alleles had 1 of these 2 mutations. Microsatellite genotyping demonstrated that a common haplotype was shared by the mutant alleles for both common mutations. The authors suggested that the 2 founder mutations may be predominant among Japanese ATM mutant alleles. Telatar et al. (1998) found that 4 mutations accounted for 86 to 93% of 41 Costa Rican AT patients studied. They suggested that the Costa Rican population might be useful for analyzing the role of ATM heterozygosity in cancer. Sasaki et al. (1998) presented the results of a mutation screen in 14 unrelated AT patients, most of them Japanese. They used a hierarchical strategy in which they extensively analyzed the entire coding region of the cDNA. In the first stage, point mutations were sought by PCR-SSCP in short patches. In the second and third stages, the products of medium- and long-patch PCR, each covering the entire region, were examined by agarose gel electrophoresis to search for length changes. They found a total of 15 mutations (including 12 new) and 4 polymorphisms. Abnormal splicing of ATM was frequent among Japanese, and no hotspot was obvious, suggesting no strong founder effects in that ethnic group. Eleven patients carried either 1 homozygous or 2 compound heterozygous mutations, 1 patient carried only 1 detectable heterozygous mutation, and no mutation was found in 2 patients. Overall, mutations were found in at least 75% of the different ATM alleles examined. Sandoval et al. (1999) investigated the mutation spectrum of the ATM gene in a cohort of AT patients living in Germany. They amplified and sequenced all 66 exons and the flanking untranslated regions from genomic DNA of 66 unrelated AT patients. They identified 46 different ATM mutations and 26 sequence polymorphisms and variants scattered throughout the gene; 34 mutations had not previously been described in other populations. Seven mutations occurred in more than 1 family, but none of these accounted for more than 5 alleles in the patient group. Most of the mutations were truncating, which confirmed that the absence of full-length ATM protein is the most common molecular basis of AT. Transcript analyses demonstrated single exon skipping as the consequence of most splice site substitutions, but a more complex pattern was observed for 2 mutations. In 4 cases, immunoblot studies of cell lines carrying ATM missense substitutions or in-frame deletions detected residual ATM protein. One of these mutations, a valine deletion proximal to the kinase domain (607585.0017), resulted in ATM protein levels more than 20% of normal in an AT lymphoblastoid cell line. Castellvi-Bel et al. (1999) used SSCP analysis to screen the ATM gene in 92 AT patients from different populations. Of 177 expected mutations, approximately 70% were identified using this technique. Thirty-five new mutations and 34 new intragenic polymorphisms or rare variants were described. Laake et al. (2000) screened 41 AT families from Denmark, Finland, Norway, and Sweden for ATM mutations. They were able to characterize 67 of the 82 disease-causing alleles. Of the 37 separate mutations detected, 25 had not previously been reported. In 28 of the probands, mutations were found in both alleles; in 11 of the probands only 1 mutated allele was detected; and in 2 Finnish probands, no mutations were detected. One-third of the probands (13) were homozygous, whereas the majority of the probands (26) were compound heterozygous with at least 1 identified allele. Ten alleles were found more than once; 1 Norwegian founder mutation, 3245delATCinsTGAT (607585.0016), an insertion/deletion mutation, constituted 57% of the Norwegian alleles. Due to the large size of the ATM gene and the existence of over 400 mutations, identifying mutations in patients with ataxia-telangiectasia is labor intensive. Campbell et al. (2003) compared the single-nucleotide polymorphism (SNP) and short tandem repeat (STR) haplotypes of AT patients from varying ethnicities who were carrying common ATM mutations. They used SSCP to determine SNP haplotypes. To their surprise, all of the most common ATM mutations in their large multiethnic cohort were associated with specific SNP haplotypes, whereas the STR haplotypes varied, suggesting that ATM mutations predate STR haplotypes but not SNP haplotypes. They concluded that these frequently observed ATM mutations are not hotspots, but have occurred only once and spread with time to different ethnic populations. More generally, a combination of SNP and STR haplotyping could be used as a screening strategy for identifying mutations in other large genes by first determining the ancestral SNP and STR haplotypes in order to identify specific founder mutations. Campbell et al. (2003) estimated that this approach will identify approximately 30% of mutations in AT patients across all ethnic groups. In a mutation screen of 24 Polish AT families, Mitui et al. (2005) found that 3 founder mutations accounted for 58% of the alleles. They identified 44 (92%) of the expected 48 mutations: 69% were nonsense mutations, 23% caused aberrant splicing, and 5% were missense mutations. Four mutations had not been previously described. Two of the Polish mutations had been observed previously in Amish and Mennonite AT patients; this was considered compatible with historical records. Shared mutations had the same SNP and STR haplotypes, indicating common ancestries. See monographs edited by Bridges and Harnden (1982) and Gatti and Swift (1985) for a perspective on the development of this disorder. Anheim et al. (2010) found that AT was the third most common form of autosomal recessive cerebellar ataxia in a cohort of 102 patients evaluated in Alsace, France. Of 57 patients in whom a molecular diagnosis could be determined, 4 were affected with AT. The authors estimated the prevalence of AT to be 1 in 450,000 in this region. FRDA was the most common diagnosis, found in 36 of 57 patients, and AOA2 (606002) was the second most common diagnosis, found in 7 patients.