Founder Effect Mutation Research Articles

The frequency of Hiroshima and Nagasaki residents who are heterozygous for a founder effect mutation in the xeroderma pigmentosum A (XPA) gene

The frequency of Hiroshima and Nagasaki residents who are heterozygous for a founder effect mutation in the xeroderma pigmentosum A (XPA) gene

ATM mutations, haplotype analysis, and immunological status of Russian patients with ataxia telangiectasia

Mutations in the ATM gene are responsible for the autosomal recessive disorder, ataxia telangiectasia (A-T). Mutations in different ethnic groups are distributed along the entire length of the large, 66 exon ATM gene. In this study, A-T patients from 16 Russian families were assessed for immunological status and ATM haplotype analysis, and screened for ATM mutations. Haplotype analysis was performed to enhance the efficiency of mutation detection. Mutations predicted to cause disease were identified in 19 of 32 alleles (59%), including a truncating mutation (c.5932G>T) that was identified in 8/32 (25%) alleles both by haplotype analysis and mutation screening. This mutation has been found in low abundance in other European A-T cohorts suggesting that this founder-effect mutation may be of Russian origin. The abundance of this mutation may allow for large-scale screening of cancer patients to help clarify the role of ATM in breast and other cancers. Nine of the remaining mutations were previously unreported, and add to the multitude of unique mutations found throughout the gene.

Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas

Background: Paragangliomas are rare and highly heritable tumours of neuroectodermal origin that often develop in the head and neck region. Germline mutations in the mitochondrial complex II genes, SDHB, SDHC,...

A Model for ATM Heterozygote Identification in a Large Population: Four Founder-Effect ATM Mutations Identify Most of Costa Rican Patients with Ataxia Telangiectasia

Ataxia telangiectasia (A-T) is an autosomal recessive disorder with a broad range of clinical manifestations and a frequency of 1:40,000–100,000 live births. Epidemiological studies have suggested that A-T heterozygotes are at an elevated risk of breast cancer. ATM mutations occur worldwide over the entire ATM gene, making it difficult to identify heterozygotes in large populations. However, some founder-effect mutations are specific for certain populations. Here, we present four mutations in Costa Rican A-T patients that accounted for 86–93% of 41 patients studied in two batches. We have developed assays for rapid detection of these four mutations which can be used diagnostically. They will also enable the Costa Rican population to be used as a model for analyzing the role of ATM heterozygosity in cancer development and other disorders.

Ataxia-Telangiectasia: Identification and Detection of Founder-Effect Mutations in the ATM Gene in Ethnic Populations

To facilitate the evaluation of ATM heterozygotes for susceptibility to other diseases, such as breast cancer, we have attempted to define the most common mutations and their frequencies in ataxia-telangiectasia (A-T) homozygotes from 10 ethnic populations. Both genomic mutations and their effects on cDNA were characterized. Protein-truncation testing of the entire ATM cDNA detected 92 (66%) truncating mutations in 140 mutant alleles screened. The haplotyping of patients with identical mutations indicates that almost all of these represent common ancestry and that very few spontaneously recurring ATM mutations exist. Assays requiring minimal amounts of genomic DNA were designed to allow rapid screening for common ethnic mutations. These rapid assays detected mutations in 76% of Costa Rican patients (3), 50% of Norwegian patients (1), 25% of Polish patients (4), and 14% of Italian patients (1), as well as in patients of Amish/Mennonite and Irish English backgrounds. Additional mutations were observed in Japanese, Utah Mormon, and African American patients. These assays should facilitate screening for A-T heterozygotes in the populations studied.

Genetic testing for ataxia-telangiectasia. • 634

The recent isolation and sequencing of the gene responsible for ataxia telangiectasia, ATM, has facilitated new insights into how genetic testing should be designed. The ATM gene is composed of 9168 nucleotides and 66 exons. Over 200 mutations have been identified in affected individuals. Most mutations (71%) result in protein truncations. Early reports describe changes in mRNA only; genomic mutations are still being characterized. Exon skipping in mRNA is frequently observed. However, even when the same exon is skipped in mRNA from two patients, the underlying genomic mutations may differ. Most patients who are not the offspring of a consanguineous mating are compound heterozygotes, i.e., they carry two distinct mutations. Most mutations are unique and they are distributed across the entire gene. For prenatal testing, in families with a prior affected child in whom the mutations remain unidentified, DNA haplotyping of all members of the immediate family is still the most efficient approach. If one mutation has been identified in the family, haplotyping can be circumvented if that mutation is found to be unambiguously absent in the fetal DNA sample. In extended families or ethnic populations in whom the founder effect mutation has been identified, rapid assays are being developed that can be performed on large numbers of individuals. These assays also allow accurate diagnosis of heterozygotes and screening of cancer prone populations. Rapid assays are presently available for Amish, Moroccan Jews, Norwegian (detects 60% of Norwegian patients) Costa Rican (65%), Polish (30%), and Italian (10%). Heterozygote identification for individuals without a prior affected relative is still problematic and will most likely require an automated approach to genetic testing.

Diversity of ATM gene mutations detected in patients with ataxia‐telangiectasia

The ataxia-telangiectasia mutated (ATM) gene, which is mutated in the autosomal recessive disorder ataxia-telangiectasia (AT), was isolated in 1995 by positional cloning. Although in vitro cell fusion studies had suggested that AT was genetically heterogeneous, all AT patients studied to date have been found to harbor mutations in the ATM gene. More than 100 ATM mutations occurring in AT patients have been documented. The mutations are broadly distributed throughout the ATM gene. Except for patients from families with known consanguinity, most AT patients are compound heterozygotes. The majority (>70%) of mutations are predicted to lead to protein truncation. A significant number of the reported mutations affect mRNA splicing with at least half of the coding exons (32/62) having been observed to undergo exon skipping. The large size of the ATM gene, 66 exons spanning ˜150 kb of genomic DNA, together with the diversity and broad distribution of mutations in AT patients greatly limits the utility of direct mutation screening as a diagnostic tool, or method of carrier identification, except where founder effect mutations are involved. Hum Mutat 10:100–107, 1997. © 1997 Wiley-Liss, Inc.

Diversity of ATM gene mutations detected in patients with ataxia-telangiectasia.

The ataxia-telangiectasia mutated (ATM) gene, which is mutated in the autosomal recessive disorder ataxia-telangiectasia (AT), was isolated in 1995 by positional cloning. Although in vitro cell fusion studies had suggested that AT was genetically heterogeneous, all AT patients studied to date have been found to harbor mutations in the ATM gene. More that 100 ATM mutations occurring in AT patients have been documented. The mutations are broadly distributed throughout the ATM gene. Except for patients from families with known consanguinity, most AT patients are compound heterozygotes. The majority (> 70%) of mutations are predicted to lead to protein truncation. A significant number of the reported mutations affect mRNA splicing with at least half of the coding exons (32/62) having been observed to undergo exon skipping. The large size of the ATM gene, 66 exons spanning approximately 150 kb of genomic DNA, together with the diversity and broad distribution of mutations in AT patients greatly limits the utility of direct mutation screening as a diagnostic tool, or method of carrier identification, except where founder effect mutations are involved.