The genetic landscape of the FAS pathway deficiencies

Dysfunction of the FAS-FASLG pathway causes a lymphoproliferative disorder with autoimmunity called Autoimmune lymphoproliferative syndrome (ALPS) mainly caused by FAS mutations. The goal of this review is to describe the genetic bases of the autoimmune lymphoproliferative syndrome and to underline their genetic complexity with the contribution of both germline and somatic events accounting for the variable clinical penetrance of the FAS mutations. Starting from the cohort of patients studied in the French cohort (>165 cases), we also reviewed the literature cases in order to depict a full description of the mutations affecting the FAS-FASLG pathway involved in the outcome of this rare nonmalignant and non-infectious pediatric lymphoproliferative disease. We also discussed the variable clinical penetrance associated with mutations affecting the extracellular domain of the protein. Such non-penetrant germline mutations are frequently associated with an additional somatic event impacting the second allele of FAS. Moreover, the uncomplete clinical penetrance associated with mutations affecting the intracellular domain of FAS, in patient lacking additional FAS somatic event, suggested a potential digenic inheritance with a FAS mutation accompanied by a genetic modifier possibly impacting another player of the lymphocytes homeostasis (affecting the survival, activation or apoptosis of the peripheral leukocytes).

Automated summary

The dysfunction of the FAS-FASLG pathway leads to Autoimmune lymphoproliferative syndrome (ALPS), primarily caused by FAS mutations. The genetic bases of ALPS are complex, involving both germline and somatic events contributing to the variable clinical manifestations of FAS mutations. Understanding the impact of mutations on the extracellular domain of FAS and the potential digenic inheritance with genetic modifiers can offer insights into the pathogenesis and clinical penetrance of this rare pediatric disease.