Abstract
Autoimmune lymphoproliferative syndrome (ALPS) is a primary immune regulatory disorder clinically defined by chronic and benign lymphoproliferation, autoimmunity and an increased risk of lymphoma due to a genetic defect in the FAS-FASL apoptotic pathway. Genetic defects associated with ALPS are germinal and somatic mutations in FAS gene, in addition to germinal mutations in FASLG, FADD, CASP8 and CASP10 genes. The accumulation of CD3+TCRαβ+CD4-CD8- double negative T-cells (DNT) is a hallmark of the disease and 20-25% of ALPS patients show heterozygous somatic mutations restricted to DNT in the FAS gene (ALPS-sFAS patients). Nowadays, somatic mutations in the FAS gene are detected through Sanger sequencing in isolated DNT. In this study, we report an ALPS-sFAS patient fulfilling clinical and laboratory ALPS criteria, who was diagnosed through NGS with a targeted gene panel using DNA from whole blood. Data analysis was carried out with Torrent Suite Software and variant detection was performed by both germinal and somatic variant caller plugin. The somatic variant caller correctly detected other six ALPS-sFAS patients previously diagnosed in the authors’ laboratories. In summary, this approach allows the detection of both germline and somatic mutations related to ALPS by NGS, avoiding the isolation of DNT as the first step. The reads of the somatic variants could be detected even in patients with DNT in the cut off limit. Thus, custom-designed NGS panel testing may be a faster and more reliable method for the diagnosis of new ALPS patients, including those with somatic FAS mutations (ALPS-sFAS).
Highlights
Autoimmune lymphoproliferative syndrome (ALPS), initially termed Canale-Smith syndrome [1], is a rare Primary Immune Regulatory Disorder (PIRD) defined by childhood onset chronic and benign lymphoproliferation, autoimmune phenomena mainly in form of multilineage cytopenia and an increased risk of lymphoma due to an impairment of lymphocyte homeostasis [2,3,4]
Combination of somatic and germinal FAS mutations, involvement of other ALPS-phenotype-modifiers genes such as UNC13D, XIAP, PRF1, CASP10, as well as numerous genetic defects outside the FAS-FAS Ligand (FASL) pathway leading to an ALPS-like phenotype have been described [10,11,12,13,14,15,16]
ALPS is mostly caused by FAS mutations either germline or somatic, being restricted mainly to double negative T-cells (DNT) in the latter case
Summary
Autoimmune lymphoproliferative syndrome (ALPS), initially termed Canale-Smith syndrome [1], is a rare Primary Immune Regulatory Disorder (PIRD) defined by childhood onset chronic and benign lymphoproliferation, autoimmune phenomena mainly in form of multilineage cytopenia and an increased risk of lymphoma due to an impairment of lymphocyte homeostasis [2,3,4]. Lymphocyte homeostasis is affected by defective FAS-mediated apoptosis and in most ALPS patients the apoptotic defect is consequence of inherited (germline) or acquired (somatic) mutations in the FAS gene (ALPS-FAS and ALPS-sFAS patients, respectively). Germinal mutations in the FASLG (ALPSFASLG), FADD (ALPS-FADD), CASP10 (ALPS-CASP10) and CASP8 (ALPS-CASP8) genes can occur [2, 3, 5,6,7,8,9,10]. Combination of somatic and germinal FAS mutations, involvement of other ALPS-phenotype-modifiers genes such as UNC13D, XIAP, PRF1, CASP10, as well as numerous genetic defects outside the FAS-FASL pathway leading to an ALPS-like phenotype have been described [10,11,12,13,14,15,16]
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