W43 - Combined Germline and Somatic FADD Mutations as a New Cause of Autoimmune Lymphoproliferative Syndrome

Abstract Text: Autoimmune lymphoproliferative syndrome (ALPS) is characterized by splenomegaly, lymphadenopathy, hypergammaglobulinemia along with autoimmune cytopenias. Most patients with ALPS harbor FAS mono-allelic mutations, but few examples of germline bi-allelic mutations of FAS, FALG, or FADD have also been reported. To date, only six patients exhibiting FADD deficiency have been described, all with bi-allelic germline mutations. They exhibit a clinical phenotype partially overlapping with ALPS-FAS patients.
We previously discovered that germline FAS haplo-insufficient mutations can be associated with somatic events on the second FAS allele in the patients, but not in the healthy relatives carrying the germline mutation only. These second genetic events could be a somatic mutation in the second allele of FAS, or a somatic uniparental disomy resulting in a loss of heterozygosity (LOH). Those somatic events are mostly detected in the TCRab+ CD4-CD8- T cells called double negative T cells (DNTs).
Here, we report on 3 unrelated patients presenting with clinical features fulfilling the classical ALPS criteria. Whole exome sequencing revealed germline mono-allelic mutations of FADD affecting the same codon (p.R117) in all 3 patients. By analogy with our previous studies on ALPS-FAS, we sequenced DNA from sorted DNTs of 2 patients. We identified a somatic LOH resulting in homozygous FADD mutations in the DNTs subset. This is the second description indicating that auto-immune diseases can developed as the consequence of the accumulation of one germline and one somatic event.