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Estimating the age of rare disease mutations: the example of Triple-A syndrome
  1. E Genin1,
  2. A Tullio-Pelet2,
  3. F Begeot2,
  4. S Lyonnet2,
  5. L Abel3
  1. 1Génétique Epidémiologique et Structure des Populations Humaines, INSERM U535, Hôpital Paul Brousse, BP 1000, 94 817 Villejuif Cedex, France
  2. 2Handicaps Génétiques de l’Enfant, INSERM U393, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France
  3. 3Génétique Humaine des Maladies Infectieuses, Université René Descartes INSERM U550, Faculté de Médecine Necker, 156 rue de Vaugirard, 75015 Paris, France
  1. Correspondence to:
 Dr L Abel
 Laboratoire de Génétique Humaine des Maladies Infectieuses, INSERM U550, Faculté de Médecine Necker, 156 rue de Vaugirard, 75015 Paris, France;

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Triple-A syndrome (MIM 231550) is an autosomal recessive disorder characterised by adrenocorticotrophin hormone resistant adrenal insufficiency, achalasia of the oesophageal cardia, and alacrima.1 The gene, previously localised to chromosome 12q13,2,3 was recently identified and denoted as AAAS.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.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. Different methods have been proposed to estimate the age of mutations,5,6 which are based either on allele frequencies7 or on intra-allelic variability and the pattern of linkage disequilibrium at closely linked marker loci8,9 with extensions to the analysis of multilocus data.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. 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+1G→A mutation.


Method of dating

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 basic assumption is that the two affected individuals descend from a common ancestor who introduced the mutation ngen generations …

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  • This work was supported by Fondation BNP-Paribas, Fondation pour la Recherche Médicale, Fondation Schlumberger, and Délégation à la Recherche Clinique (Grant CRC00114).

  • Conflicts of interest: none declared.