Autoimmune Lymphoproliferative Syndrome via the FAS Gene

Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder characterized by dysregulation of lymphocyte hemostasis resulting in elevation of non-malignant lymphocyte numbers. Affected individuals present with lymphadenopathy, hepatomegaly, and splenomegaly during the first years of life. In the second decade of life, patients often experience autoimmune attacks on red blood cells (hemolytic anemia), neutrophils (neutropenia), or platelets (thrombocytopenia) due to production of autoantibodies. Other symptoms may include arthritis, vasculitis, oral ulcers, skin rash, and heightened risk for development of lymphoma (Bleesing et al. 2011). Homozygous affected patients display severe forms of the disease with lymphoproliferation leading to autoimmune disease and/or lymphoma early in life. ALPS is caused by mutations in either the FAS (~75%), FASLG (<5%), or CASP10 (<5%) gene. Patients with ALPS may be treated with immunosuppressive therapies such as corticosteroids to maintain lymphocyte homeostasis (Rao and Oliveira 2011). Genetic testing is helpful in differential diagnosis of ALPS from other immune disorders such as common variable immunodeficiency disease, Hyper IgM syndrome (Test #1653), X-linked lymphoproliferative disease, Wiskott-Aldrich syndrome (Test #440) and from other forms of ALPS (Bleesing et al. 2011).

ALPS is inherited in an autosomal dominant manner through mutations in either the FAS, FASLG, or CASP10 gene. Mutations in the FAS gene primarily occur in the germline for individuals with ALPS (~70% of cases) but can also occur somatically in double negative (CD4-CD8-) α/β T cells (~15% of cases) leading to disease (Neven et al. 2011; Holzelova et al. 2004). Homozygous and compound heterozygous mutations in the FAS gene have been reported in ALPS patients with severe disease. Mutations in the FASLG or CASP10 gene each account for <5% of cases of ALPS. Mutations are found throughout the FAS gene with the majority occurring within exons 7-9 which encode the intracellular domains of Fas and lead to dominant negative functional effects (Fisher et al. 1995). Missense (40% cases), nonsense (15%), splice site (20%), and small insertion/deletions (18%) have all been reported to be causative for ALPS (NIAID ALPS Database). Penetrance for defective Fas-mediated apoptosis is 100%, but clinical penetrance is variable as relatives heterozygous for disease causing mutations have been reported to lack ALPS clinical symptoms (Jackson et al. 1999). The FAS gene encodes the Fas receptor which binds its ligand, FasL. This receptor ligand interaction is essential controlling lymphocyte populations by facilitating apoptosis to prevent autoimmune disease and non-malignant lymphoproliferation (Bleesing et al. 2011).

Mutations in the FAS gene account for ~75% cases of ALPS. Detection of germ line mutations in the FAS gene in patients meeting strict ALPS criteria is 65-70% (Bleesing et al. 2011). Identification of somatically acquired FAS mutations is best performed on DNA extracted from flow cytometric sorted double negative (CD4-CD8-) α/β T cells, but may also be detected through sequencing analysis from a standard blood draw (Magerus-Chatinet et al. 2009). Analytical sensitivity is >99% as full gene deletions have not been reported in the FAS gene to date (NIAID ALPS Database).

This test provides full coverage of all coding exons of the FAS gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).