Estimating the age of rare disease mutations: the example of Triple-A syndrome.

T riple-A syndrome (MIM 231550) is an autosomal recessive disorder characterised by adrenocorticotrophin hormone resistant adrenal insufficiency, achalasia of the oesophageal cardia, and alacrima. The gene, previously localised to chromosome 12q13, 3 was recently identified and denoted as AAAS. Among the five homozygous truncating mutations that were characterised, a single splice donor splice mutation (IVS14+1GRA) was found in several unrelated affected individuals of north African origin, strongly suggesting a founder effect. 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. Different methods have been proposed to estimate the age of mutations, 6 which are based either on allele frequencies or on intraallelic variability and the pattern of linkage disequilibrium at closely linked marker loci 9 with extensions to the analysis of multilocus data. 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. 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. The method was tested through simulations and then applied to nine consanguineous Triple-A patients, who were homozygous for the IVS14+1GRA mutation.