Prenatal genotyping of ataxia-telangiectasia

Gatti, Richard A.; Peterson, Kristin L.; Novak, Jessica; Chen, Xiaoguan; Yang-Chen, Lan; Liang, Teresa; Lange, Ethan M.; Lange, Kenneth

doi:10.1016/0140-6736(93)91525-q

Cited by 24 publications

(9 citation statements)

References 3 publications

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“…This combined approach is thought to yield a false negative rate of ≪1% [123]. For presymptomatic diagnosis of A‐T family members, including prenatal diagnosis, haplotype analysis has supplanted other tests [124].…”

Section: Diagnosis and Treatment Of A‐tmentioning

confidence: 99%

Ataxia‐telangiectasia, cancer and the pathobiology of the ATM gene

1999

Clinical Genetics

203

147

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Ataxia-telangiectasia (A-T) is a pleiotropic inherited disease characterized by neurodegeneration, cancer, immunodeficiencies, radiation sensitivity, and genetic instability. Although A-T homozygotes are rare, the A-T gene may play a role in sporadic breast cancer and leukemia. ATM, the gene responsible for A-T, is homologous to several cell cycle checkpoint genes from other organisms. ATM is thought to play a crucial role in a signal transduction network that modulates cell cycle checkpoints, genetic recombination, apoptosis, and other cellular responses to DNA damage. New insights into the pathobiology of A-T have been provided by the creation of Atm-/- mice and by in vitro studies of ATM function. Analyses of ATM mutations in A-T patients and in sporadic tumors suggest the existence of two classes of ATM mutation: null mutations that lead to A-T and dominant negative missense mutations that may predispose to cancer in the heterozygous state.

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Section: Diagnosis and Treatment Of A‐tmentioning

confidence: 99%

Ataxia‐telangiectasia, cancer and the pathobiology of the ATM gene

1999

Clinical Genetics

203

147

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“…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.…”

Section: Introductionmentioning

confidence: 99%

ATM Gene Founder Haplotypes and Associated Mutations in Polish Families with Ataxia‐Telangiectasia

Mitui

Bernatowska

Pietrucha

et al. 2005

Annals of Human Genetics

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SummaryAtaxia-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.

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“…After the mapping of the ataxia telangiectasia gene and the recovery of its flanking polymorphisms, a more reliable-if also indirect-prenatal diagnosis was performed at the molecular level by genotyping the fetus for these markers (Gatti et al, 1993;Tverskaya et al, 1997). The use of microsatellites very close to the affected gene allowed the determination of the haplotype associated with the diseased paternal and maternal ATM alleles, making it possible to predict the genotype of the fetus.…”

Section: Discussionmentioning

confidence: 99%

“…The disease gene was cloned in 1995 and called ATM (Ataxia Telangiectasia Mutated) (Savitsky et al, 1995). Owing to the severity of the disease, prenatal diagnosis has been attempted in the past via the clastogenicity of the AT amniotic fluid (Shaham et al, 1982), biochemical parameters (Auerbach, 1987), chromosomal instability (Schwartz et al, 1985;Llerena et al, 1989), radio-resistant DNA synthesis (Jaspers et al, 1990;Kleijer et al, 1994), and at molecular level by genotyping the fetus for flanking polymorphisms (Gatti et al, 1993;Tverskaya et al, 1997). Ataxia telangiectasia is rare but not infrequent in Italy; 110 families are recorded in the Italian Registry for AT (Chessa et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Molecular prenatal diagnosis of ataxia telangiectasia heterozygosity by direct mutational assays

et al. 1999

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Ataxia telangiectasia (AT) is a severe autosomal recessive disease, rare but not infrequent in Italy. Owing to the seriousness of the disease, prenatal diagnosis has been attempted in the past by means of cytogenetic, biochemical, radio‐biological and indirect molecular analyses. We performed the first direct molecular prenatal diagnosis of AT on a chorionic villi sample from a 37‐year‐old woman at the 10th week of pregnancy. She had two previous children suffering AT and two induced abortions. At molecular analysis her affected children were compound heterozygotes for mutations 7792C→T in exon 55 (from the mother) and 8283delTC in exon 59 (from the father). The prenatal diagnosis was performed by two different operators in double‐blind form. Mutation 7792C→T was studied by restriction enzyme analysis using TaqI. Mutation 8283delTC was screened by heteroduplex analysis. The fetus was heterozygous for the mutation 7792C→T (confirmed by sequencing). In order to verify the possible contamination by maternal DNA, polymorphic loci HLA‐DRB1 and HLA‐DQA1, together with microsatellite markers D6S259, D11S2000, D11S29, D11S1778 and D11S2179, were examined. All these loci were informative, showing that the fetus received only one allele from each parent. The heterozygosity for ATM mutation 7792C→T was confirmed by molecular studies after the birth of a healthy male baby. Copyright © 1999 John Wiley & Sons, Ltd.

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Prenatal genotyping of ataxia-telangiectasia

Cited by 24 publications

References 3 publications

Ataxia‐telangiectasia, cancer and the pathobiology of the ATM gene

Ataxia‐telangiectasia, cancer and the pathobiology of the ATM gene

ATM Gene Founder Haplotypes and Associated Mutations in Polish Families with Ataxia‐Telangiectasia

Molecular prenatal diagnosis of ataxia telangiectasia heterozygosity by direct mutational assays

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