Autoimmune Lymphoproliferative Syndrome (ALPS) in Indian Population: Clinical, and Immunological Diversity in Genes Related to FAS-Mediated Apoptotic Pathway

Autoimmune lymphoproliferative syndrome (ALPS) is an immune-mediated disorder caused by defects affecting the FAS-mediated apoptotic pathway, particularly FAS , FASLG and FADD. Other defects in this pathway including CASP8 , and CASP10 , may cause overlapping phenotypes but are not uniformly classified as classical ALPS. While FAS mutations are well-documented, data on the rarer ALPS subtypes remain limited. This study systematically evaluated 31 individuals, identified by next-generation sequencing, with defects affecting the Fas-mediated apoptotic pathway by analysing their molecular, clinical, and immunological features. FAS variants accounted for 41.93% of cases, followed by FADD (25.80%), FASLG (12.90%), CASP8 (6.45%), CASP10 (3.22%), and ALPS-U (9.67%). Lymphoproliferation and autoimmune cytopenias were predominant, although atypical manifestations such as colitis and auto-inflammatory phenotypes were noted. Immunophenotypic analyses revealed elevated DNTs, expanded Fas-controlled DNTs, and mTOR hyperactivity in most cases, whereas CASP8 and CASP10 variants displayed distinct immune profiles. Apoptosis defects were observed in FAS , FADD , CASP8 , and ALPS-U, while FASLG variants demonstrated normal apoptosis and low sFASL levels. FAS mutations were identified in homozygous, heterozygous, and somatic forms and exhibited a dominant negative mechanism with variable penetrance. Two families with homozygous FADD variants presented novel phenotypes. Treatments included MMF and sirolimus, with one CASP8 patient undergoing successful HSCT. This is the first comprehensive study of ALPS from India highlighting the genetic and immunological heterogeneity of classical ALPS and other disorders affecting the FAS-mediated apoptotic pathway.