Case Report: A Novel Pathogenic Missense Mutation in FAS: A Multi-Generational Case Series of Autoimmune Lymphoproliferative Syndrome

Abstract

Autoimmune Lymphoproliferative Syndrome (ALPS), commonly caused by mutations in the FAS gene, is a disease with variable penetrance. Subjects may be asymptomatic, or they may present with lymphadenopathy, splenomegaly, cytopenias, or malignancy. Prompt recognition of ALPS is needed for optimal management. We describe a multi-generational cohort presenting with clinical manifestations of ALPS, and a previously unreported heterozygous missense variant of uncertain significance in FAS (c.758G >T, p.G253V), located in exon 9. Knowledge of the underlying genetic defect permitted prompt targeted therapy to treat acute episodes of cytopenia. This cohort underscores the importance of genetic testing in subjects with clinical features of ALPS and should facilitate the reclassification of this variant as pathogenic.

Case Report: Deficiency of Adenosine Deaminase 2 Presenting With Overlapping Features of Autoimmune Lymphoproliferative Syndrome and Bone Marrow Failure

“…In addition, the coexistence of strongly diminished ADA2 activity with an oligosymptomatic phenotype in the sister can be explained by well-known intrafamilial phenotypic variability despite the same underlying homozygous mutations (11,19,30,(36)(37)(38)(39)(40). However, even if individuals with biallelic ADA2/CECR1 pathogenic variants were reported to have remained asymptomatic until adulthood or to have never developed clinical manifestations of DADA2 (41), the sister of our patient is currently following up with another adult rheumatology center.…”

ALPS, FAS, and beyond: from inborn errors of immunity to acquired immunodeficiencies

“…Hence, a double-hit mechanism (i.e., predisposing germline mutations followed by disease-triggering somatic mutations) has been hypothesized [19]. Moreover, the variable penetrance seen in ALPS patients' pedigrees [20] suggested that a digenic model of inheritance could be applicable, due to a possible role of disease-modifying genes [21]. Finally, variants in FAS and FASL have been reported in patients displaying multifactorial autoimmune diseases and cancer (e.g., systemic lupus erythematosus, SLE) [13,[22][23][24].…”

“…ALPS patients' pedigrees often show an incomplete disease penetrance [20,63]. However, additional genetic mechanisms may come into play and ultimately determine the expression of an ALPS disease phenotype [1,17].…”

“…Germline mutations in FASL and CASP10 , together with germline or somatic mutations in FAS , give rise to typical ALPS clinical and laboratory features [ 18 , 20 , 31 , 32 ] and have therefore been included in ALPS classification [ 9 ]. On the other hand, mutations in FADD and CASP8 lead both to an impairment in FAS-mediated apoptosis and a profound susceptibility to infections [ 33 , 34 ].…”

“…Hence, a double-hit mechanism (i.e., predisposing germline mutations followed by disease-triggering somatic mutations) has been hypothesized [ 19 ]. Moreover, the variable penetrance seen in ALPS patients’ pedigrees [ 20 ] suggested that a digenic model of inheritance could be applicable, due to a possible role of disease-modifying genes [ 21 ].…”