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PubMed1998

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.

Ataxia Telangiectasia↗
PubMed1999

Prenatal diagnosis and the subsequent mutation analysis in a family with carbohydrate-deficient glycoprotein type I syndrome: growing evidence to support founder effects within CDG1 populations.

Carbohydrate deficient-glycoprotein syndrome type I (CDG1 or Jaeken Syndrome) is an autosomal recessive multisystem disease with severe early involvement of the nervous system. Mutations in the phosphomannomutase 2 (PMM2) gene have recently been identified in 16 affected individuals. In the current study, we have described a CDG1 family where gene tracking had been used to perform prenatal diagnosis before the isolation of the CDG1 gene. Haplotype analysis indicated that the unborn child had inherited the maternal 'normal' allele, but a critical recombination event meant that it was impossible to determine if the child had inherited the paternal mutation. Single-strand conformation polymorphism and sequence analysis revealed that the mother was a carrier of a C-->A transversion at position 357 (F119L), and that the father was a carrier of a G-->A transition at position 425 (R141H). The unborn child had inherited the paternal R141H mutation. Because only three mutations have previously been reported in UK families, of which F119L and R141H are two, and given that there is evidence of allelic association in CDG1 families, it is possible that a limited number of ancestral mutations have given rise to most cases of CDG1 in any one population.

Chromosomes, Human, Pair 16↗
PubMed1993

The high frequency of TTR M30 in familial amyloidotic polyneuropathy is not due to a founder effect.

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disease due to mutations in the transthyretin (TTR) gene. Valine30-->methionine (TTR M30) is by far the most common mutation in patients with FAP. In a sample of 11 North American unrelated patients, we previously found that 6 had TTR M30. By utilizing double PASA, we could perform haplotype analysis despite the absence of DNA samples on relatives. The results indicate that at least four of the six patients with TTR M30 have different haplotypes, an observation that is surprising for North American patients in which the ostensible symptoms generally begin after the reproductive years. It is suggested that the most likely explanation is rapid selection against TTR M30 mutations by one of four possible mechanisms.

Amino Acid Sequence↗
PubMed1996

A recurrent homozygous nonsense mutation within the LAMA3 gene as a cause of Herlitz junctional epidermolysis bullosa in patients of Pakistani ancestry: evidence for a founder effect.

The anchoring filament protein laminin 5 is abnormally expressed in the skin of patients with Herlitz junctional epidermolysis bullosa (H-JEB). In this study, we performed mutational analysis on genomic DNA from a H-JEB child of first-cousin Pakistani parents, and identified a homozygous C-to-T transition in the LAMA3 gene of laminin 5 resulting in a premature termination codon (CGA-TGA) on both alleles. This mutation, R650X, has been previously reported in two other seemingly unrelated H-JEB individuals of Pakistani ancestry. Although this mutation may represent a mutational hotspot within the LAMA3 gene, haplotype analysis based on a silent intragenic polymorphism (GCC/GCG, alanine 429; GenBank no. L34155), and on three flanking microsatellite polymorphism (D18S45, D18S478, and D18S480), suggests that a common ancestral allele may be present in all three cases.

Base Sequence↗
PubMed2002

Congenital central hypothyroidism due to homozygous thyrotropin beta 313 Delta T mutation is caused by a Founder effect.

Neonatal TSH screening has been a major achievement for the early detection and treatment of primary congenital hypothyroidism. It nevertheless fails to reveal cases of central hypothyroidism caused by TSH levels in the low normal range. In the last 10 yr, homozygous mutations in the TSHbeta-subunit gene have been recognized as a cause of central hypothyroidism with isolated TSH deficiency. The most frequent TSHbeta mutation 313DeltaT (C105V) has been described in six apparently unrelated families. We investigated the frequency and possible monophyletic origin of the different TSHbeta 313DeltaT alleles of the three affected families. Haplotype analysis of five polymorphic single-nucleotide polymorphism loci in the TSHbeta region revealed the presence of seven different haplotypes in the general population. In all six parental lines, the mutation occurred on the same haplotype. Extending the haplotype by two flanking microsatellite markers led to a mutational age estimate of about 150 generations. In 500 unrelated individuals from the general population, we did not detect any TSHbeta 313DeltaT allele, suggesting a population heterozygote carrier frequency less than 1:170 with more than 95% probability. Accordingly, the disease risk in the general population because of homozygosity is low. Our data suggest a monophyletic origin of the TSHbeta 313DeltaT mutation from a common ancestor and no significant population prevalence. Therefore, identification and genetic counseling of heterozygous carriers in affected families seems to be more advisable than population-wide neonatal T(4) screening programs for an early detection of this rare condition.

Alleles↗