IMD2; SCNX; THC; THC1; WASP; WASPA
The WAS gene is associated with X-linked recessive Wiskott-Aldrich syndrome (MedGen UID: 21921), severe congenital neutropenia (MedGen UID: 335314) and thrombocytopenia (MedGen UID: 326416), collectively known as WAS-related disorders.
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The percentage of bone marrow failure attributed to pathogenic variants identified in WAS is unknown.
The WAS gene encodes the WASP cytoplasmic protein, which is primarily expressed in hematopoietic cells. WASP is part of a family of proteins that relay signals from receptors on the cell surface to the actin cytoskeleton.
WAS-related disorders, caused by pathogenic variants in the WAS gene, represent a spectrum of conditions ranging from the severe Wiskott-Aldrich syndrome (WAS), to the milder clinical variations of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN). The age of onset for these disorders is typically in infancy, and symptoms are often present at birth (PMID: 26159751). All males with WAS-related disorders are expected to develop symptoms, although there is marked variability in phenotypic expression (PMID: 16630926, 20301357).
Classic Wiskott-Aldrich syndrome is defined by thrombocytopenia with small platelets, recurrent infections due to immunodeficiency, and eczema, although two-thirds of affected individuals do not exhibit this triad of symptoms (PMID: 26159751). The majority (84%) of individuals with WAS have bleeding, which is life-threatening in 30% of cases (PMID: 16630926). Presenting symptoms may include petechiae, bruising, bloody diarrhea, and excessive bleeding following circumcision. Common infections include otitis media, skin infections and bacterial pneumonia (PMID: 19147084).
The immunophenotype associated with WAS may include lymphopenia, with the absolute number of lymphocytes decreasing over time; functional abnormalities of T cells may manifest as abnormal proliferative responses to mitogens. Immunoglobulin (Ig) M and IgG may be decreased, and IgA and IgE may be elevated (PMID: 24817816).
Autoimmune disorders are common, observed in 40% of affected individuals, and may include autoimmune hemolytic anemia, vasculitis, renal disease, inflammatory bowel disease, immune thrombocytopenia purpura (ITP), and rheumatoid arthritis, among others (PMID: 12819473, 16630926). There is an increased incidence of hematopoietic malignancies, (affecting 13% of patients in one cohort) including EBV-associated B-cell and T-cell lymphomas, Hodgkin lymphoma, myelodysplasia and leukemia (PMID: 7996359, 19147084).
The XLT variant of WAS includes microthrombocytopenia, which may be chronic or intermittent. Life expectancy is not typically compromised, although severe infections (7%), bleeding (14%), autoimmune diseases (12%), and malignancies (5%) may cause significant morbidity (PMID: 20173115).
XLN is characterized by severe congenital neutropenia, monocytopenia, increased myeloid cell apoptosis, and lymphoid cell abnormalities (PMID: 20301357). XLN is associated with an increased risk of myelodysplastic syndrome and acute myelogenous leukemia.
Genotype-phenotype correlations in WAS-related disorders have been reported, but genotype alone is an unreliable predictor of disease (PMID: 20301357). WASP protein expression has been suggested to be a more reliable predictor of clinical phenotype; in one study, the majority of individuals with absent WASP protein expression were diagnosed with Wiskott-Aldrich syndrome while those with residual WASP expression had X-linked thrombocytopenia (PMID: 25931402). X-linked neutropenia is caused by pathogenic gain-of-function variants affecting the CDC42-binding domain of WASP (PMID: 16630926, 26159751). It is important to note, however, that WAS-related disorders constitute a spectrum of diseases rather than distinct clinical entities.
Female carriers of a pathogenic variant in WAS rarely have significant clinical symptoms and generally have no immunologic or biochemical markers of the disorder; however, some may have mild thrombocytopenia. Rarely, females may have symptoms of Wiskott-Aldrich syndrome due to skewed X-inactivation (PMID: 24817816, 23943155).
The WAS gene encodes the WASP cytoplasmic protein, which is expressed in hematopoietic cells. WASP is part of a family of proteins that relay signals from receptors on the cell surface to the actin cytoskeleton (NCBI: https://www.ncbi.nlm.nih.gov/protein/NP_000368.1 Accessed February 2017). WASP signaling triggers white blood cell motility and adhesion during infection by pathogenic bacteria. Evidence suggests WASP is a regulator of lymphocyte and platelet function (UniProtKB – P42768 (WASP_HUMAN); http://www.uniprot.org/uniprot/P42768 Accessed February 2017).
Pathogenic variants in the WAS gene follow X-linked recessive inheritance. A female with a pathogenic variant has a 50% chance of passing the variant on to her offspring. Males who inherit a pathogenic variant will be affected, and females who inherit a pathogenic variant will be carriers. Males with a pathogenic variant will pass it to all of their daughters, who will be carriers, while none of their sons will inherit the variant. Most males with WAS-related disorders inherited a pathogenic variant from a carrier mother, but approximately one third of cases occur spontaneously (PMID: 20301357). In these cases, even though the affected male did not inherit the pathogenic variant from his mother, he has a chance to pass it on to future offspring. With a positive result, it is possible to identify at-risk relatives who can pursue testing for the specific familial variant.
Following the initial diagnosis of a WAS-related disorder, timely referral to an immunologist for medical management is appropriate. Affected individuals are best served by seeking care through a clinic experienced in the management of primary immune deficiencies; these clinics often employ a multidisciplinary approach, including consultation with transplant immunology, hematology/oncology, critical care, infectious disease and medical genetics (PMID 24817816).
Treatment options vary depending on the clinical presentation of the affected individual. For Wiskott-Aldrich syndrome, hematopoietic cell transplantation (HCT) is the only curative therapy, with 84-91% of males receiving HCT in favorable conditions being cured (PMID: 21659547, 22426750). Topical steroids are typically used for eczema, and antibiotics for treatment of infections. Autoimmune disease is treated with immunosuppressants (PMID: 20301357).
Widely accepted treatment policies for individuals with XLT have not been established. While survival is excellent with rigorous management of symptoms, serious complications such as severe bleeding episodes, autoimmune disease, malignancy or serious infection persist throughout life (PMID: 20173115). The use of hematopoietic cell transplantation may be considered for individuals with an identical human leukocyte antigen matched donor, however risks and benefits of HCT must be carefully weighed (PMID: 20173115). HCT is generally considered on a case by case basis for individuals with XLT. Individuals with X-linked neutropenia are often managed with granulocyte colon-stimulating factor and antibiotics (PMID: 26159751).
Prophylactic antibiotics may be used for prevention of pneumonia. Intravenous immunoglobulin replacement therapy (IVIg) is administered at regular intervals after 6 months of age (PMID: 20301357). Live vaccines should not be given to individuals with WAS-related disorders (PMID: 16630926).
Identification of a pathogenic WAS variant confirms the diagnosis of a WAS-related disorder. The appropriate treatment and management of WAS-related disorders is imperative for a positive clinical outcome. In addition to enabling treatment for the affected individual, at-risk relatives can be informed about genetic risks and pursue genetic testing, if desired.
Review date: February 2017
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Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
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