The following is a summary of “Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome,” published in the January 2024 issue of Allergy & Immunology by Pellé, et al.
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by noninfectious, nonmalignant lymphoproliferative disease often linked to autoimmune cytopenia due to defective FAS signaling. Previously, germline monoallelic FAS (TNFRSF6) haploinsufficient mutations associated with somatic events, like loss of heterozygosity on the second allele of FAS, were identified as causing ALPS-FAS. These somatic events were detected by sequencing FAS in DNA from double-negative (DN) T cells, the characteristic T-cell subset in ALPS, where such events accumulated. For a study, researchers sought to ascertain if a somatic event affecting the FAS-associated death domain (FADD) gene could be implicated in disease onset in four unrelated ALPS patients harboring a germline monoallelic mutation of the FADD protein inherited from a healthy parent.
Sequencing of FADD and array-based comparative genomic hybridization using DNA from sorted CD4+ or DN T cells were conducted.
Homozygous FADD mutations arising from uniparental disomy were identified in DN T cells from all four patients. FADD deficiency resulting from germline heterozygous FADD mutations, coupled with somatic loss of heterozygosity, mimicked ALPS-FAS without the broader symptomatology seen in patients with germline biallelic FADD mutations.
The interplay between germline and somatic events impacting the FADD gene represented a novel genetic mechanism underlying ALPS.
Reference: jacionline.org/article/S0091-6749(23)01209-5/abstract