A Missense Mutation in the Extracellular Domain of Fas: The Most Common Change in Argentinean Patients with Autoimmune Lymphoproliferative Syndrome Represents a Founder Effect

Mutations in the Fas gene ( TNFRSF6 ) are the most common causes of Autoimmune Lymphoproliferative Syndrome (ALPS-FAS). Purpose In Argentina almost a third of patients with ALPS-FAS present a missense mutation affecting the extracellular cysteine rich domain 2 of Fas, p.Cys107Tyr (C107Y). This change was found in homozygous state in 2 patients from a consanguineous family, and heterozygously, in 3 other patients from 3 unrelated families. In these families, 12 relatives were identified as healthy carriers of the mutation. We sought to test the hypothesis that this mutation actually represents a single haplotype of TNFRSF6 . Methods DNAs from ALPS-C107Y patients and their families, as well as from 150 Argentinean control subjects were sequenced for the known higher frequency single nucleotide polymorphisms (SNPs) of TNFRSF6 . The C107Y-carriers were also genotyped at 5 microsatellites proximal to the Fas gene locus. Results All C107Y alleles presented a unique intragenic haplotype that could be restricted to this group. Extent of haplotype sharing and variability of microsatellite alleles in C107Y chromosomes support the presence of a single haplotype block including the mutation and encompassing 2.395 Mb. Conclusions A founder effect for C107Y has been evidenced in this work and the most common recent ancestor to the patients probably lived 350 years ago. This constitutes the first report of a founder event in ALPS.