Inborn Errors of Immunity/Primary Immunodeficiency (PID) Panel

There are currently over 400 different inborn errors of immunity, also referred to as primary immunodeficiencies (PID) that range in severity and age of onset. PIDs, when considered individually, were previously considered rare diseases with an incidence ranging from ~1 in 10,000 to 1 in 50,000 births; however, when considered collectively and with improved definitions of clinical phenotypes and newborn screening the incidence may be closer to ~1 in 1,000 to 1 in 5,000 births (Griffith et al. 2016. PubMed ID: 27262745; Tangye et al. 2020. PubMed ID: 31953710). 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, and/or malignancy (Tangye et al. 2020. PubMed ID: 31953710). However, many PIDs have overlapping symptoms making diagnosis challenging. Different therapeutics may be utilized to manage the various diseases (Griffith et al. 2016. PubMed ID: 27262745). Many acquired or secondary PIDs can be caused by malnutrition, infections, environmental stress, drugs, surgery or trauma.

Of note, a PID classification phone app that is based on the International Union of Immunological Societies committee report is available for use (PID Phenotypical Diagnosis App). This app allows one to explore the various PIDs by searching classification tables, specific PIDs, or clinical manifestations.

This test includes genes identified through literature, OMIM, and HGMD searches that have a reported association with PIDs. 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 (Picard et al. 2018. PubMed ID: 29226302; Bousfiha et al. 2018. PubMed ID: 29226301; Tangye et al. 2020. PubMed ID: 31953710).

Inborn errors of immunity 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.

One study analyzed the clinical efficacy of a 242 gene PID panel and determined that of the 27 individuals with symptoms suggestive of a PID 48% (13/27) received a monogenic diagnosis (Rae et al. 2018. PubMed ID: 29077208). Another study analyzed causative PID genes in infants less than three months old with infections or abnormal white blood cell counts and identified 2.13% of the cohort had an undiagnosed PID (Sun et al. 2020. PubMed ID: 32431812). Another study utilized clinical exome sequencing in individuals with a suspected PID and determined a molecular diagnosis in 31% of the cohort, however 20% had variants in known PID genes while 11% had variants in other genes (Rudilla et al. 2019. PubMed ID: 31681265).

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: GPIBA, 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).