• ATM mutations;
  • Polish;
  • Amish;
  • Mennonite;
  • Haplotypes


  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

Ataxia-telangiectasia (A-T) is an early onset autosomal recessive ataxia associated with characteristic chromosomal aberrations, cell cycle checkpoint defects, cancer susceptibility, and sensitivity to ionizing radiation. We utilized the protein truncation test (PTT), and single strand conformation polymorphism (SSCP) on cDNA, as well as denaturing high performance liquid chromatography (dHPLC) on genomic DNA (gDNA) to screen for mutations in 24 Polish A-T families. Twenty-six distinct Short Tandem Repeat (STR) haplotypes were identified. Three founder mutations accounted for 58% of the alleles. Three-quarters of the families had at least one recurring (shared) mutation, which was somewhat surprising given the low frequency of consanguinity in Poland. STR haplotyping greatly improved the efficiency of mutation detection. We identified 44 of the expected 48 mutations (92%): sixty-nine percent were nonsense mutations, 23% caused aberrant splicing, and 5% were missense mutations. Four mutations have not been previously described. Two of the Polish mutations have been observed previously in Amish and Mennonite A-T patients; this is compatible with historical records. Shared mutations shared the same Single Nucleotide Polymorphism (SNP) and STR haplotypes, indicating common ancestries. The Mennonite mutation, 5932 G>T, is common in Russian A-T families, and the STR haplovariants are the same in both Poland and Russia. Attempts to correlate phenotypes with genotypes were inconclusive due to the limited numbers of patients with identical mutations.


  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

Ataxia-telangiectasia (A-T; MIM # 208900) is an autosomal recessive, neurological disorder with a frequency of 1/40 000–1/100 000 (Gatti, 2002). Cerebellar ataxia, immunodeficiency, oculocutaneous telangiectasia, and radiation sensitivity are characteristic findings in A-T patients. These patients also have a greatly increased risk of cancer (Gatti & Good, 1971; Swift et al. 1986). They typically manifest premature aging, degeneration of the cerebellum, thymus and gonads, growth retardation, and telomere shortening (Gatti, 2002; Chun & Gatti 2004). Carrier frequencies of ATM mutations have been estimated as 1–1.8% and are proving significant with regard to breast cancer susceptibility (Swift et al. 1987; Easton, 1994; Gatti et al. 1999; Concannon, 2002; Buchholz et al. 2004).

A-T is caused by mutations in the Ataxia-Telangiectasia Mutated gene (ATM) located at 11q23.1 (Gatti et al. 1988; Lange et al. 1995; Savitsky et al. 1995). The ATM gene is over 150 kb in size and includes 62 coding exons, encoding a 13 kb main transcript, with an open reading frame of 9168 bp (Uziel et al. 1996; Platzer et al. 1997). The ATM protein is 370 kDa, is found predominantly in the cell nucleus, and is a protein serine/threonine kinase (Shiloh, 2003; Bakkenist & Kasdan, 2003).

A-T patients are typically compound heterozygotes carrying unique mutations, and no “hot spots” in the ATM gene have been found (Mitui et al. 2003). Therefore, the entire gene must be screened to determine the two disease-causing mutations for each patient. Our strategy for ATM mutation screening has been to first perform SNP and STR haplotyping (Mitui et al. 2003; Coutinho et al. 2004), followed by PTT (Telatar et al. 1996; Den Dunnen et al. 1999), SSCP (Castellvi-Bel et al. 1999) or dHPLC (Bernstein et al. 2003). Finally, each relevant genomic region is sequenced to identify the mutation.

Previous studies have shown that STR haplotyping can greatly increase mutation detection in ethnic populations by associating founder mutations with their STR haplotypes (Uhrhammer et al. 1995; Telatar et al. 1998; Laake et al. 1998; Ejima et al. 1998; Campbell et al. 2003; Mitui et al. 2003; Coutinho et al. 2004; Babaei et al. 2005; Birrell et al. 2005). Haplotyping is also useful for prenatal testing and occasionally for heterozygote identification within A-T families (Gatti et al. 1993). Herein we studied twenty-four Polish families with A-T and found that three founder mutations recurred (were shared) in 58% of the families, and nine recurring founder haplotypes accounted for 83% of the families. Mutations were identified for all founder haplotypes.

Materials and Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References


Twenty-four unrelated A-T families from Poland comprised this study group. All patients displayed classical A-T phenotypes. Lymphoblastoid cell lines (LCLs) were established for most of the probands. The diagnosis was confirmed by the absence of the ATM protein by immunoblotting and the finding of radiosensitivity by a colony survival assay (Sun et al. 2002); at least one ATM mutation was also identified for each proband. Family WAR 49 included two affected sibs. Blood collection followed approved Human Subject Protection protocols in Poland and the United States.

Haplotype Analysis

STR haplotyping was used to first determine whether founder mutations were present in the Polish population, thus minimizing the number of mutations that would have to be screened. As previously described (Mitui et al. 2003), STR haplotypes were identified using four markers: S1819 (Rotman et al. 1994), NS22 (Udar et al. 1999), S2179 (Vanagaite et al. 1995), and S1818 (Rotman et al. 1994). Markers NS22 and S2179 are located within the ATM gene; markers S1819 and S1818 flank the gene within 1.4 cM on the proximal and distal ends, respectively. PCR amplified end-radiolabelled fragments were run on 6% polyacrylamide gel (National Diagnostics, Atlanta, Georgia) and compared with a known control (CEPH1347-2) (Mitui et al. 2003). This control has allowed the allele sizes to be standardized so that haplotypes from various ethnic populations could be compared (Mitui et al. 2003; Coutinho et al. 2004; Birrell et al. 2005). Haplotype phase was defined using parents or by comparing haplotypes of patients with the same mutation.

SNP haplotyping was carried out by SSCP (Castellvi-Bel et al. 1999), using three SNP markers: IVS17-56G>C, 5557G>A, and IVS62-55T>C. These three SNPs defined the three most common SNP haplotypes across the ATM region (H2, H3 and H4), which encompass 91% of SNP haplotypes worldwide (Thorstenson et al. 2001; Campbell et al. 2003). The more uncommon Haplotype H1 was also identified in two families.

Mutation Detection

Mutation screening was performed with PTT (Telatar et al. 1996) followed by SSCP (Castelvi-Bel et al. 1999) and dHPLC (Bernstein et al. 2003). PTT detects truncating mutations, such as nonsense mutations, frameshifts caused by small insertions or deletions, or aberrant splicing (Telatar et al. 1996; Teraoka et al. 1999). SSCP was used to further identify abnormal regions in the cDNA of the ATM gene. Sequencing changes were revealed by a measurable difference in mobility through a gel, due to differences in the secondary structure of single stranded cDNA or genomic DNA (Castellvi-Bel et al. 1999). This technique used 34 overlapping fragments to cover the gene, with each fragment spanning ∼300 nt of coding sequence. dHPLC was performed on samples that still had one mutation unidentified after the PTT and SSCP screening. Candidate regions were sequenced in both directions and the mutated site identified using genomic DNA.


  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References


Twenty-six distinct STR haplotypes were observed in 24 ostensibly unrelated Polish families. The incidence of homozygosity was very low; only two probands had homozygous haplotypes and mutations, WAR 12 and WAR 31 (Figure 1). Nine haplotypes were observed in more than one family, encompassing 83% of the families. The Polish A-T population proved to be more homogeneous than expected, as 83% of the families carried at least one founder haplotypes (Figure 1A). Indeed, the three most common haplotypes, [A], [B], and [D], occurred in 14 of the 24 families (58%).


Figure 1. Haplotypes and mutations in 24 Polish A-T families. A. Recurring haplotypes are colour shaded. The 〈〉 indicate that phase has not been defined. B. Mutations corresponding to the affected haplotypes in A. Bold mutations have not been previously reported. Conserved amino acids are underlined. Superscripts: a, first allele; b, second allele; h: homozygous. Asterisk denotes a primary premature termination codon (PTC). Nucleotide numbering is based on +1 being the A of the initiation start codon.

With few exceptions, STR haplotypes are conserved between A-T patients with the same mutation (Campbell et al. 2003). We observed this to be true for markers NS22 and S2179. However, some variation was found for S1819, and to a lesser degree S1818. This most likely reflects the instability of STR markers or could be due to polymerase slippage in some cases. Occasional recombination outside the gene is also possible, although recombination within the gene is very uncommon (Bonnen et al. 2000; Thorstenson et al. 2001). Variant STR haplotypes (haplovariants) were observed for some patients carrying the same mutation. For example, haplotype [G] of WAR2 and WAR15, carried the 3085_3086insA mutation. Another example can be seen with WAR 31, where the S1818 alleles differ in a family with consanguineous history. WAR33 was more difficult to interpret: the mutation (IVS53-2A>C) and the H3 SNP haplotype remained unchanged as compared to other patients (e.g., WAR 24), while the STR haplotype was different for S2179, similar to changes observed by Campbell et al. (2003). It was not possible to define phase in WAR16.

SNP haplotypes H1, H2, H3, and H4 were identified in the Polish population. SNP haplotype frequencies in Poland were similar to previously described worldwide SNP haplotype frequencies (Throstenson et al. 2001). H2 was the most common haplotype (41%). H3 was found in 33%; this is higher than the global frequency of 12%. The H4 frequency was lower than expected (20% vs 40%). H1 was seen in association with two distinct STR haplotypes (WAR 23 and WAR 49) and two distinct mutations. This haplotype is uncommon outside of Africa (Thorstenson et al. 2001; Coutinho et al. 2004).


Mutations were detected in 44 of 48 alleles (92%). Of 21 different mutations, 15 were truncating, 5 aberrant splicing, and 1 missense (Figure 1B). The most common mutation, IVS53-21<C, a splicing mutation, was found in 7 of 48 chromosomes (14.6%) and was associated with Haplotype [A]. The second and third most common mutations, 5932G>T and 6095G>A, were each found in 5 and 4 chromosomes (10% and 8%), in association with Haplotypes [D] and [B], respectively. Only three mutations were novel; however, our laboratory has also previously published other unique Polish mutations (Telatar et al. 1998).

Mutation 5932G>T results in GAA>TAA or premature termination condon. However, a small proportion of the transcript is missing all of exon 42 (88nt), suggesting that the mutation may also lead to aberrant splicing. This mutation was observed in five of the families, on three haplovariants. Two of the haplovariants have been observed in Russian A-T families as well (Birrell et al. 2005).

Genotypes versus Phenotypes

Serum alphafetoprotein (AFP) levels were elevated in all 24 patients. Similarly, all patients tested lacked detectable intranuclear levels of ATM protein. None of the genotype/phenotype comparisons were significantly different, due to the limited number of patients in each group and the paucity of homozygous patients; none of the patients carrying haplotypes [A], [B] or [D] were homozygous. A summary of the clinical dataset is presented in Table 1.

Table 1.  Genotype/phenotype comparisons
  1. Progression of ataxia 1 = slow, 2 = moderate, 3 = rapid

  2. *The family of WAR 49 includes two affected children.

  3. Immunoglobulins were increased on at least two occasions.

Number of patients (N)75*525*
Male: Female4:33:23:210:14
Ataxia onset (years old) (0.9–7 yrs)
Progression of ataxia1.71.421.6
Wheelchair (%N)5710010067
Wheelchair (years old)15141214 (9–19 yrs)
Telangiectasia onset (years old)3.663.44 (2–7 yrs)
Growth Retardation (%N)57205050
Mental Retardation (%N)43202029
Bronchiectasia (%N)43602029
Cancer (%N)0008.7
IVIg therapy (%N)57806050
AFP elevated (%N)100100100100
AFP (IU/ml)276107147208
IgM [UPWARDS ARROW] (%N)160256
IgA [DOWNWARDS ARROW] (%N)664010045
IgE [DOWNWARDS ARROW] (%N)801006796

Haplotype [A], carrying IVS53-2A>C, was observed in seven patients; none were homozygous. The average age of onset of ataxia was 2.0 years and the average age of onset of telangiectasia was 3.6 years. Of the seven patients with this mutation, three were not yet confined to a wheelchair (all were under 10 years old); the other four patients were wheelchair bound but were older, averaging 15 years of age when they became wheelchair dependent. No other phenotype differences were apparent.

Haplotype [B], carrying 6095G>A, affected five patients (two of whom were sibs in family WAR 49; only one is shown in Fig 1). The average age of ataxia onset was 3.1 years, with greater variation than for haplotype [A]. Within this group, the WAR 49 sibs did not have telangiectasia at ages 14 and 15. The average age of onset for the other three patients was 6 years. All five patients required a wheelchair by an average age of 14.

Haplotype [D], carrying 5932G>T, affected 5 patients; the average age of ataxia onset was 1.3 years. This average was almost identical to that of the Russian A-T families (Birrell et al. 2005).


  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

Due to the large size of the ATM gene and the broad spectrum of ATM mutations, mutation detection is not yet cost-effective for establishing a diagnosis of A-T. In this study, the diagnosis was confirmed by a lack of ATM protein western blotting and radiosensitivity on by CSA, in all patients. Serum AFP levels were elevated in all patients. Thus, these aspects of the A-T phenotype were not influenced by genotype in any apparent way.

We observed that 58% of the A-T families in Poland shared one of three founder mutations (Haplotype [A], [B], and [D]), and 83% of the families carried at least one of eight Polish founder haplotypes. We were surprised to find this degree of genetic homogeneity, considering that Polish population migrations have not been restricted by geographical features such as large bodies of water or high mountain ranges. Nonetheless, our previous studies of ATM haplotypes and mutations strongly suggest that shared, recurring mutations predate modern ethnicities and nationalities (Campbell et al. 2003), and STR haplotypes such as [A], [B], and [D] may reflect influences on ancient migrations rather than on modern ones. Eleven Polish ATM mutations have also been found in other ethnic groups (Table 2).

Table 2. 
MutationAlso found in
1563_1564delAGAmish, Turkish, Italian, German, Brazilian
IVS20–579_IVS20–582delAAGTGerman, American-Hispanic
5712_5713insAPhillippino, Turkish,
5932G>TNorwegian, Danish, Mennonite, American-Hispanic, German, Russian
6095G>ASwedish, German, French
IVS53-2A>CDanish, American-Hispanic, Brazilian, Portuguese

Splicing mutations comprised 23% of the mutations found in this study, a proportion not unlike those in previous studies (Teraoka et al. 1999; Mitui et al. 2003). Splicing mutations typically involve the highly conserved canonical 3′ or 5′ splice sites, as is the case for IVS 53-2A>C on Polish haplotype [A]. Three other splicing mutations were noted on non-recurring Polish haplotypes. IVS20–597delAAGT is a ‘masked’ mutation that causes Type II splicing with pseudoexon formation (Eng et al. 2004). The mutation occurs deep within intron 20, and disrupts the U6 portion of a U1 snRNA binding site (Pagani et al. 2002). It has also been observed in German, Turkish and Hispanic-American patients (Mitui et al. 2003; Eng et al. 2004); the standardized STR haplotypes of the Hispanic-American families differ slightly from those of the Old World (Polish, German, Turkish) A-T families (Eng et al. 2004), providing further evidence that many ATM mutations predate STR haplotypes, but not the common SNP haplotypes (Thorstenson et al. 2001; Campbell et al. 2003)

Most ATM mutations are associated with specific STR and SNP haplotypes (Campbell et al. 2003; Mitui et al. 2003; Eng et al. 2004). This held true without exception for the SNP haplotypes associated with Polish mutations. In general, this was also true for the association of these mutations with STR haplotypes, with two exceptions: in WAR33 [A][D] and WAR 19 [B][E]. WAR33 carries the Haplotype [A] mutation, IVS53-2A>C; however, the S2179 allele appears to have changed from ‘141’ to ‘139’. The H3 SNP haplotype background remains the same as that observed for all [A] haplovariants in this study. Haplovariants were also observed for the 5932 G>T mutation on Haplotype [D] (see below) and for the 6095G>A mutation on Haplotype [B]. Both long and short forms of this Haplotype [B] were observed (Fig 1A), with only a single allele (S2179 ‘137’) shared by all four chromosomes (WAR 6, 19, 22, and 49–3). Taken together, these data suggest that the longest variant (eg: WAR 49–3) is the older, ancestral haplotype for this mutation, although alternative interpretations are possible.

The mutation on Haplotype [F], 1563_1564delAG, is perhaps the most commonly observed ATM mutation worldwide and always occurs on a SNP H2 background. It was observed in three Polish families in association with SNP haplotype (H2), but with several STR haplovariants. As previously described (Campbell et al. 2003), 1563_1564delAG is associated with STR haplovariant 1 (in Turkish, Polish and Amish A-T patients), haplovariant 2 (in a Brazilian patient), and haplovariant 3 (in Turkish and Italian patients). In all of these families, the allele for S1818 was ‘160’, as is also observed in two of the Polish families; however, in WAR 46, a new haplovariant 4 was defined by allele S1818 ‘158’ (instead of ‘160’). These findings are compatible with the historical origins of the Amish of Pennsylvania (U.S.A) from Germanic settlers, descendants of an Anabaptist movement in northern Europe (1525–1536) (Hostetler, 1983a).

The mutation 5932G>T, found on Polish Haplotype [D], has also been observed in Mennonites, another Germanic Christian sect of Anabaptist roots that settled in Kentucky and Pennsylvania. In the early 1500s, Mennonites from the Netherlands and North Germany migrated to the Vistula Detta (now Poland) and later continued their migrations to Canada and the United States (1873–74; 1922–30) (Hostetler, 1983b). This mutation has also been found in A-T patients from Denmark, England and Guatemala, always in association with a SNP (H2) haplotype as previously described (Campbell et al. 2003). It has recently been reported to be the most common founder mutation (44%) in a group of Russian A-T families, and the STR haplotypes are the same (Birrell et al. 2005). Alleles at S1819 vary as either ‘131’ or ‘135’, thereby defining two haplovariants that are found in both Russia and Poland.

We attempted to correlate clinical data with specific mutations. Such genotype/phenotype correlations are difficult to achieve unless several important criteria are met: (1) the classical diagnosis must be confirmed on a molecular basis to distinguish variant A-T phenotypes from other phenotypically similar diseases; (2) a sufficient number of patients must be homozygous for a mutation so that the genotypic effects can be isolated from other ATM alleles. Unless one postulates that a heterozygous mutation will have a dominant interfering effect (in which case one parent should manifest symptoms), comparing compound heterozygous patients who share only a single mutation is not likely to reveal significant genotype/phenotype correlations. Despite this, a dominant interfering effect for at least one ATM mutation (2546delSRI) has been demonstrated in the mouse both in vivo and ex vivo, with some suggestion that parent carriers of this mutation may manifest an increased incidence of cancer (Concannon, 2002; Scott et al. 2002; Spring et al. 2002). The Polish data set contained only two homozygous patients (WAR 12 and WAR 31) and neither of these haplotypes was observed in other families. Only Haplotypes [A], [D], and [B] were observed repeatedly in 7, 5, and 4 patients, respectively, and no significant genotype/phenotype correlations were noted. The entire clinical dataset is included in Table 1 so that it might later contribute to a meta-analysis of a larger cohort of A-T patients. This Table also suggests parameters for planning such analyses.

Mutation detection for the Polish A-T population was performed with the hope that it would be of assistance in counselling Polish families for family planning, prenatal diagnosis, and identification of heterozygote carriers. This information may also help in diagnosing A-T patients at a younger age by SNP and STR haplotype prescreening for the eight recurring Polish founder haplotypes. Certain types of mutations (asterisked in the ‘consequence’ column of Figure 1B) may be amenable to therapeutic intervention with aminoglycosides or other compounds (Lai et al. 2004). Lastly, understanding the spectrum of ATM mutations in Polish patients with A-T allows these mutations to be sought in breast cancer and other diseases.


  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References
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