Ataxia-Telangiectasia: Identification and Detection of Founder-Effect Mutations in the ATM Gene in Ethnic Populations Milhan Telatar, Sharon Teraoka,

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Ataxia-Telangiectasia: Identification and Detection of Founder-Effect Mutations in the ATM Gene in Ethnic Populations Milhan Telatar, Sharon Teraoka, Zhijun Wang, Helen H. Chun, Teresa Liang, Sergi Castellvi-Bel, Nitin Udar, Anne-Lise Borresen-Dale, Luciana Chessa, Eva Bernatowska-Matuszkiewicz, Oscar Porras, Mitsunori Watanabe, Anne Junker, Patrick Concannon, Richard A. Gatti The American Journal of Human Genetics Volume 62, Issue 1, Pages 86-97 (January 1998) DOI: 10.1086/301673 Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 1 Spectrum of ATM mutations, based on 205 mutations. Boxes represent founder-effect mutations, identified by shared haplotypes. The American Journal of Human Genetics 1998 62, 86-97DOI: (10.1086/301673) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 2 Protein truncation test results. a, Norwegian patients: PTT-screening region g. Lane 1 shows results for a normal control, and lanes 2 and 3 show results for patients with truncated protein of 33 kD (one homozygous, the other heterozygous). b, Costa Rican patients: PTT-screening region b. Lane 1 shows results for a normal control, and lanes 2 and 3 show results for homozygous patients with truncated protein of 25 kD. The American Journal of Human Genetics 1998 62, 86-97DOI: (10.1086/301673) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 3 Heteroduplex and haplotype analysis of a Norwegian family. Lane 1 is a heteroduplex mixture of DNA from an affected child and a normal child, lane 2 is the affected child alone, and lanes 3–5 are heterozygotes. Bracketed letters indicate corresponding haplotypes. Parents (lanes 4 and 5) carry the same mutation; consanguinity was denied. The American Journal of Human Genetics 1998 62, 86-97DOI: (10.1086/301673) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 4 Sau3AI digestion of 11 PCR products from Costa Rican patients. Lanes 1 and 15 are undigested (U) samples, and lanes 2 and 14 are digested normals (N); lanes 3–10 are A-T patients who were homozygous for haplotype A and are homozygous for the 5908C→T mutation, as indicated by the undigested bands. Lanes 11–13 are compound heterozygotes showing both digested and undigested bands. The American Journal of Human Genetics 1998 62, 86-97DOI: (10.1086/301673) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 5 Comparison of Polish mutations and haplotypes. U = undigested DNA, and N = normal control. a, Haplotype A mutation, IVS53-2A→C. Lanes 3–5 are heterozygous patient samples, and lane 6 is a patient with a cDNA deletion of exon 54 who does not have the IVS53-2A→C genomic mutation. Haplotype analysis shows that patients in lanes 3–5 share haplotype A (data shown in f), whereas the patient in lane 6 does not share this haplotype (data not shown). b, Haplotype B mutation, 6095G→A(2003del89nt). Three heterozygous Polish patients (lanes 3–5) have the 6095G→A(2003del89nt) mutation in exon 43. c, Haplotype C mutation, 7010delGT. Lanes 1 and 2 are patients who have the 7010delGT mutation in exon 50. Lanes 3 and 4 are patients who do not have this mutation. d, Haplotype D mutation, 5932G→T. MseI digestion assay was performed on samples from six Polish patients (lanes 3–8). Lanes 4 and 8 are patients with the 5932G→T mutation in exon 42. e, 3214G→T mutation. Assay was performed on samples from three Polish patients (lanes 1–3). Lane 1 is a patient with the 3214G→T mutation in exon 24. f, Haplotype analysis of the 10 Polish patients described above. Shaded areas represent four shared haplotypes (A–D). The American Journal of Human Genetics 1998 62, 86-97DOI: (10.1086/301673) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 6 Heteroduplex and haplotype analysis of two homozygous Italian patients showing the 7517del4 mutation (Savitsky et al. 1995a). Lanes 1a and 2a are the patient samples; lanes 1b and 2b are the heteroduplex mixture of DNAs from normal individuals with those of patients 1a and 2a, respectively; and lane 3 is a normal control. Haplotype analysis has shown that both patients share both haplotypes at chromosome 11q23.1. The American Journal of Human Genetics 1998 62, 86-97DOI: (10.1086/301673) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 7 Heteroduplex and haplotype analysis of a consanguineous Amish family showing the inheritance of the 1563delAG mutation. Haplotype analysis has shown that the mutation is inherited through haplotypes B and C (Lange et al. 1993). Heteroduplex analysis confirms that any person in the family with either haplotype B or haplotype C is a carrier for the mutation. The American Journal of Human Genetics 1998 62, 86-97DOI: (10.1086/301673) Copyright © 1998 The American Society of Human Genetics Terms and Conditions