PGmax^TM - Primary Immunodeficiency and Malignancy Predisposition Panel

Primary immunodeficiencies (PID), or inborn errors of immunity, are a heterogenous group of disorders with an incidence of ~1 in 1,000 to 1 in 5,000 births (Griffith et al. 2016. PubMed ID: 27262745; Tangye et al. 2020. PubMed ID: 31953710). There are currently over 400 different PIDs that range in phenotypic severity and age of onset. PIDs encompass a variety of different disorder subclasses including antibody deficiencies, autoinflammatory disorders, combined immunodeficiencies, diseases of immune dysregulation, congenital defects in phagocyte function or numbers, defects in innate immunity, complement deficiencies, and phenocopies of inborn errors of immunity (Picard et al. 2018. PubMed ID: 29226302; Bousfiha et al. 2018. PubMed ID: 29226301; Tangye et al. 2020. PubMed ID: 31953710). Overall, PIDs are associated with an increased susceptibility to infectious disease, autoimmunity, autoinflammatory diseases, allergy, or malignancy (Tangye et al. 2020. PubMed ID: 31953710).

After infections, malignancy in PID patients is the second-highest cause of death in children and adults (Riaz et al. 2019. PubMed ID: 31057537). Some PIDs have a higher susceptibility to malignancy than others, specifically common variable immunodeficiency (CVID), combined immunodeficiencies affecting cellular immunity (especially DNA repair defects), or those that impair immune regulatory control (Riaz et al. 2019. PubMed ID: 31057537). Data from the United States Immune Deficiency Network (USIDNET) registry identified a 1.42-fold excess relative risk of cancer in individuals with PID as compared to age-adjusted controls (Mayor et al. 2018. PubMed ID: 28606585). There was a significant increase in lymphoma in both men and women with PID, while there was no significant increase in the incidence of lung, color, breast, or prostate cancers in the PID patients. 

Lymphoid malignancies are cancers that originate from cells of the immune system, lymphocytes. These malignancies may include non-Hodgkin lymphoma, Hodgkin lymphoma, myeloma, and lymphocytic leukemia. Lymphomas account for two-thirds of all malignancies reported in PID patients (Filipovich et al. 1992. PubMed ID: 1327508; Mayor et al. 2018. PubMed ID: 28606585) and more in individuals with either combined immunodeficiency, DNA repair defects, or antibody deficiencies (Filipovich et al. 1992. PubMed ID: 1327508; Vajdic et al. 2010. PubMed ID: 20466855; Riaz et al. 2019. PubMed ID: 31057537). Most lymphomas reported in relation to PID are B cell lymphomas; however, T cell lymphomas have been reported in a few studies and are generally associated with chromosomal breakage disorders or cartilage hair hypoplasia (Riaz et al. 2019. PubMed ID: 31057537). There may be a higher prevalence of T cell lymphoma in patients with secondary immunodeficiencies; however, this finding may be a result of treatment bias (Nijland et al. 2018. PubMed ID: 29269521). Due to poor prognosis and complex therapeutics approaches, the management of lymphoma in patients with a PID is difficult (Herber et al. 2020. PubMed ID: 31580160).

This test includes genes identified through literature, OMIM, and HGMD searches that have a reported association with PIDs and lymphoid malignancy predisposition. In addition, this panel includes genes associated with a variety of inborn errors of immunity as described by the International Union of Immunological Societies Primary Immunodeficiency Diseases Committee are also included (Picard et al. 2018. PubMed ID: 29226302; Bousfiha et al. 2020. PubMed ID: 32048120; Tangye et al. 2020. PubMed ID: 31953710).

Disorders leading to immunodeficiency and a lymphoid malignancy predisposition are genetically heterogeneous disorders. Disorders may be inherited in an autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) manner or may arise de novo. Causative variants may include missense, nonsense, splicing, regulatory, or copy number alterations.

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

Due to the genetic heterogeneity of the disorders tested in this panel, the clinical sensitivity of this specific grouping of genes is difficult to estimate. Clinical sensitivity varies depending on the underlying immunodeficiency and malignancy.

Of note, of individuals within the USIDNET registry, CVID was the most common PID diagnosis (35%), followed by chronic granulomatous disease (13%), DiGeorge syndrome (12%), severe combined immunodeficiency (SCID, 7%), Wiskott-Aldrich syndrome (WAS, 7%), and Hyper IgM syndrome (4%). Due to the genetic heterogeneity associated with PID, no clear information on clinical sensitivity was able to be determined from the USIDNET data.

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

This panel typically provides 97.6% 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. 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).

Due to the complexity of the region, there is limited coverage for the following genes: DDX11, F8, GP1BA, IKBKG, PI4KA, RANBP2, RPS17, and UPS18.

The report will include pathogenic and likely pathogenic variants that may not be related to the patient's phenotype, but may indicate carrier status for an autosomal recessive disorder or a predisposition for an autosomal dominant disorder included on the panel. However, the report will not include all the observed rare variants of uncertain significance due to the large number of genes included in this panel. Variants of uncertain significance and risk variants that are considered to contribute to the patient's phenotype will be reported. CNVs that are found to encompass all or part of a gene(s) that is known or possibly associated with the patient’s phenotype will also be reported. A list of all rare variants included in this panel is available along with our interpretations upon request.

Reports will consist of two different sections:

• Variants in genes known to be associated with the provided phenotype

• Variants in genes possibly associated with the provided phenotype

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).