We applied the method to the analysis of nine patients with Triple-A, who were carriers of the IVS14+1G→A mutation, and found an age estimate of ≈1000–1175 years. Through simulation studies, we show that the method provided satisfactory results even with small samples (≈5 individuals), and investigate the influence on age estimates of misspecification of both allele frequencies and mutation rates at the marker loci. We first developed a simple likelihood based method to estimate the age of the most recent common ancestor of the patients, based on the information provided by haplotypes shared by affected individuals. Although different methods have been proposed to estimate the age of relatively common mutations, none of these methods has been evaluated in the context of rare monogenic diseases such as Triple-A syndrome. Therefore, we define:Īmong the causing mutations that were recently characterised in Triple-A syndrome (MIM 231550), the IVS14+1G→A mutation was found in several unrelated affected individuals of north African origin, strongly suggesting a founder effect. The problem can be understood as a survival analysis problem in which the starting point is the disease locus, the discrete time scale is the genetic distance, and the event of interest is the occurrence of a recombination. M k is the first marker on the right side for which the two individuals have different alleles. Let ( M 1., M x., M k), be a set of k ordered markers that have been typed on the right side of D, which are located at recombination fractions ( θ 1., θ x., θ k) from D. For simplicity, we will describe the method for only one side, the right side, as the treatment for the other side is completely analogous and independent. The problem is to estimate n gen from the size of the haplotype shared by the two individuals on each side of D.
The basic assumption is that the two affected individuals descend from a common ancestor who introduced the mutation n gen generations ago. We will first describe the principle of the method for two affected individuals who carry the studied mutation at the disease locus D, and then extend the method to a sample of N affected individuals. The method was tested through simulations and then applied to nine consanguineous Triple-A patients, who were homozygous for the IVS14+1G→A mutation. Therefore, we developed a new simple method based on likelihood that uses multilocus marker data to estimate the age of the most recent common ancestor of the mutation from a small number of patients. 9– 12 However, these latter approaches are dedicated more to the fine mapping of the mutation, and may not be appropriate for estimating the age of rare mutant alleles that are only found in very few affected individuals. Different methods have been proposed to estimate the age of mutations, 5, 6 which are based either on allele frequencies 7 or on intra-allelic variability and the pattern of linkage disequilibrium at closely linked marker loci 8, 9 with extensions to the analysis of multilocus data. 4 In this work, we were interested in estimating the time at which the mutation occurred, since this is expected to provide interesting and helpful information on its natural history. 4 Among the five homozygous truncating mutations that were characterised, a single splice donor splice mutation (IVS14+1G→A) was found in several unrelated affected individuals of north African origin, strongly suggesting a founder effect. 1 The gene, previously localised to chromosome 12q13, 2, 3 was recently identified and denoted as AAAS. Triple-A syndrome (MIM 231550) is an autosomal recessive disorder characterised by adrenocorticotrophin hormone resistant adrenal insufficiency, achalasia of the oesophageal cardia, and alacrima.
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