Autoimmune Lymphoproliferative Syndrome/ALPS Panel

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 primarily in 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., 2017. PubMed ID: 20301287). Adult forms of ALPS have recently been described with some individuals developing life threatening end organ lymphoproliferative disease (Niemela et al., 2011. PubMed ID: 21079152). Patients with ALPS may be treated with immunosuppressive therapies such as corticosteroids to maintain lymphocyte homeostasis (Rao and Oliveira, 2011. PubMed ID: 21885601). There are 5 different subtypes of ALPS distinguished by their underlying genetic cause: type 1A (FAS), type2B (FASLG), type 2A (CASP10), type 2B (CASP8), type 3 (PRKCD), type 4 (NRAS, KRAS), and type 5 (CTLA4). Genetic testing is helpful in identifying the subtype of ALPS as well as in differential diagnosis from other immune disorders. Other related disorders include common variable immunodeficiency disease (CVID), Hyper IgM syndrome, X-linked lymphoproliferative diseases, Wiskott-Aldrich syndrome and FADD deficiency, autoimmune disease multisystem infantile onset type 1/ADMIO1, and activated PI3K-δ syndrome type 1/APDS1 (Bleesing et al., 2017. PubMed ID: 20301287; Sumegi et al., 2000. PubMed ID: 11049992; Li et al., 2014. PubMed ID: 24550228; Linka et al., 2012. PubMed ID: 22289921; Stepensky et al., 2011. PubMed ID: 21109689; Bolze et al., 2010. PubMed ID: 21109225; Chun et al., 2002. PubMed ID: 12353035).

ALPS is inherited in an autosomal dominant manner through pathogenic variants in either the FAS, FASLG, or CASP10 genes. Pathogenic variants 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-) a/b T cells (~15% of cases) leading to disease (Neven et al., 2011. PubMed ID: 21885602; Holzelova et al., 2004. PubMed ID: 15459302). Homozygous and compound heterozygous pathogenic variants in the FAS gene have been reported for ALPS with patients having severe disease. Pathogenic variants in the CASP10 or FASLG gene account for <5% and <1% of cases of ALPS respectively (Bleesing et al., 2017. PubMed ID: 20301287). A germline NRAS or somatic KRAS gain of function variant, designated p.Gly13Asp, has been reported in rare cases of ALPS (Oliveira et al., 2007. PubMed ID: 17517660; Niemela et al., 2011. PubMed ID: 21079152; Takagi et al., 2011. PubMed ID: 21063026). Gain of function pathogenic variants within the STAT3 and PIK3CD genes are responsible for ADMIO1 and APDS2 respectively, whereas loss of function pathogenic variants result in immunodeficiency syndromes (Angulo et al., 2013. PubMed ID: 24136356; Lucas et al., 2013. PubMed ID: 24165795; Haapaniemi et al., 2015. PubMed ID: 25349174). Disorders and inheritance patterns of other lymphoproliferative disorders are listed below.

Apoptosis is an important process for maintaining lymphocyte homeostasis allowing responses to pathogens but avoiding autoimmune effects. Many of the genes involved in this panel facilitate apoptosis through a Fas-associated mechanism resulting in a cascade of caspase activation.

Germline pathogenic variants in the FAS, FASLG and CASP10 genes account for about 75%, <5% and <5% of Autoimmune Lymphoproliferative Syndrome (ALPS) cases respectively. Somatic FAS variants account for about 15-20% of cases. Currently about 20% of cases of ALPS have an undefined genetic cause (Shah et al., 2014. PubMed ID: 25086580; Bleesing et al., 2017. PubMed ID: 20301287). Clinical sensitivity for the CASP8, FADD, ITK, KRAS, MAGT1, and NRAS genes for ALPS is currently unknown due to limited number of cases reported to date. Around 60% of X-linked Lymphoproliferative syndrome cases are attributed to pathogenic variants in the SH2D1A gene. Large deletions account for approximately 25% of all reported SH2D1A pathogenic variants (Arico et al., 2001. PubMed ID: 11159547).

Gross deletions in the FAS gene have only been reported in a few cases (Magerus-Chatinet et al., 2011. PubMed ID: 21183795; Pensati et al., 1997. PubMed ID: 9322534; van der Werff ten Bosch et al., 1998. PubMed ID: 9695976). Gain of function pathogenic variants in the STAT3, KRAS and NRAS genes have been reported to be causative for ALPS, and deletion/duplication testing has minimal clinical utility. Large deletions account for approximately 25% of all reported SH2D1A pathogenic variants (Arico et al., 2001. PubMed ID: 11159547). Large deletions in XIAP have been reported in Familial Hemophagocytic Lymphohistiocytosis patients, but make up < 10% of all reported XIAP pathogenic variants (Marsh et al., 2009. PubMed ID: 19398375).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 coverage as >20X NGS reads or Sanger sequencing. Only exons 5, 10, 11, 14 and 21-23 will be analyzed for the STAT3 as only gain of function variants in these regions have been reported for patients with ADMIO1.

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).