Primary Immunodeficiency Genetic Panel: Immune Disorder Genes and Results

A primary immunodeficiency genetic panel tests many genes linked to inborn errors of immunity, a large group of disorders that can cause unusual infections, autoimmunity, inflammation, allergy, abnormal blood cells, lymphoproliferation, or cancer susceptibility. The panel can confirm a suspected diagnosis, clarify inheritance, guide targeted treatment, identify relatives who need testing, and help plan stem cell transplantation or gene therapy in selected conditions. It is not a stand-alone immune function test. A pathogenic variant must fit the person’s symptoms, laboratory immune profile, and inheritance pattern. A negative result does not rule out an immune disorder because hundreds of genes are known, new disorders continue to be discovered, and some variants are difficult for standard panels to detect. A variant of uncertain significance should not be treated as a diagnosis. Testing usually uses blood or saliva and needs no fasting, but a blood sample may be preferred when acquired blood-cell variants, mosaicism, or prior stem cell transplantation could complicate interpretation.

• A pathogenic result can establish a molecular diagnosis and may change infection prevention, immune treatment, transplant planning, or family testing.
• A negative panel does not exclude an inborn error of immunity or replace immunoglobulins, vaccine responses, blood counts, and lymphocyte testing.
• A variant of uncertain significance is inconclusive and should not direct major treatment without additional evidence.
• Testing is most useful when ordered with a detailed infection, autoimmune, inflammatory, allergy, cancer, and family history.
• Infants with severe infection, persistent thrush, profound lymphopenia, or an abnormal SCID newborn screen need urgent specialist evaluation before genetic results return.

Table of Contents

• What the genetic panel covers
• Clinical signs that may lead to testing
• Choosing a panel, exome, or genome test
• Sample collection and laboratory methods
• How to interpret the result
• How a diagnosis can change care
• Inheritance and family testing
• Next steps after a negative or uncertain result

What the genetic panel covers

Inborn errors of immunity, formerly called primary immunodeficiencies, include hundreds of genetic disorders. Some weaken defense against many pathogens. Others create narrow susceptibility to one type of bacterium, virus, fungus, or parasite. Many also cause excessive inflammation, autoimmune disease, severe allergy, abnormal lymphocyte growth, bone marrow failure, or cancer.

Modern classification groups these disorders by immune phenotype, including:

• combined immunodeficiencies affecting T cells and often B cells;
• combined immunodeficiency with syndromic features;
• predominantly antibody deficiencies;
• immune dysregulation disorders;
• defects of phagocyte number or function;
• defects in intrinsic and innate immunity;
• autoinflammatory disorders;
• complement deficiencies;
• bone marrow failure and related syndromes;
• phenocopies caused by somatic variants or anti-cytokine autoantibodies.

A panel may contain 100, 300, 500, or more genes. Examples include IL2RG, ADA, RAG1, RAG2, JAK3, DCLRE1C, BTK, TNFRSF13B, NFKB1, CTLA4, LRBA, STAT1, STAT3, DOCK8, WAS, CYBB, GATA2, PIK3CD, PIK3R1, XIAP, SH2D1A, PRF1, UNC13D, C3, C5, and many others. The correct list depends on the phenotype.

The panel looks for DNA variants, not immune-cell performance. A person can have abnormal immunoglobulin levels or vaccine responses with no reportable panel variant. Conversely, a pathogenic variant may be found before severe laboratory abnormalities develop.

A broad panel can identify unexpected diagnoses when symptoms overlap. For example, recurrent infections plus eczema may suggest several different disorders; autoimmunity plus low immunoglobulins can arise from multiple pathways. The tradeoff is a greater chance of uncertain findings.

The SCID genetic test is a focused urgent application within this larger field. A broad panel may also include SCID genes, but immediate immune protection and transplant evaluation should not wait for sequencing when an infant is critically lymphopenic.

Clinical signs that may lead to testing

Frequent common colds alone rarely prove immune deficiency. Specialists look for infections that are unusually severe, persistent, recurrent, difficult to treat, caused by opportunistic organisms, or concentrated in specific organs. The type of pathogen can point toward the affected immune pathway.

Features that may justify genetic evaluation include:

• recurrent pneumonia, deep abscesses, sepsis, meningitis, or invasive fungal disease;
• persistent thrush, chronic diarrhea, poor growth, or severe viral infections in infancy;
• infections with unusual mycobacteria, Pneumocystis, chronic mucocutaneous Candida, or severe herpes viruses;
• repeated need for intravenous antibiotics or prolonged antimicrobial courses;
• absent tonsils or lymph nodes with very low immunoglobulins;
• unexplained lymphopenia, neutropenia, thrombocytopenia, anemia, or abnormal lymphocyte subsets;
• severe eczema, food allergy, very high IgE, or recurrent skin infections combined with other warning signs;
• early-onset autoimmunity affecting several organs;
• inflammatory bowel disease beginning in infancy or very early childhood;
• recurrent fever, sterile inflammation, vasculitis, or macrophage activation;
• persistent enlarged lymph nodes, spleen enlargement, granulomas, or lymphoma;
• characteristic physical findings, developmental differences, albinism, skeletal abnormalities, or congenital heart disease;
• several affected relatives, early unexplained childhood deaths, consanguinity, or an X-linked family pattern.

Adults can be diagnosed for the first time. Common variable immunodeficiency, activated PI3K-delta syndrome, GATA2 deficiency, CTLA4 haploinsufficiency, complement deficiency, and other conditions may appear later or vary greatly within a family.

The clinical history should include vaccines, infection organisms and cultures, imaging, antibiotic response, hospitalizations, autoimmune disease, allergies, cancers, family history, and medication exposures. Secondary immune deficiency from HIV, chemotherapy, steroids, protein loss, malnutrition, kidney disease, or blood cancer must also be considered.

Urgent warning signs include an infant with very low T cells, an abnormal T-cell receptor excision circle newborn screen, severe opportunistic infection, persistent thrush with failure to thrive, or a family history of early infant deaths. These require immediate clinical immunology involvement.

Choosing a panel, exome, or genome test

A targeted panel offers deep coverage of selected genes, clear limits, and faster interpretation. It works well when the phenotype strongly suggests an inborn error of immunity and the panel is current and comprehensive.

Exome sequencing examines most protein-coding regions across the genome. It may be preferable when immune symptoms occur with neurologic, developmental, skeletal, kidney, or other features that could point beyond a standard immune panel. Trio testing of the patient and both biological parents improves interpretation of new dominant variants and recessive inheritance.

Genome sequencing covers coding and noncoding DNA more broadly and can improve detection of some structural, intronic, and copy-number variants. It still does not detect every repeat, epigenetic change, low-level mosaic variant, or functional immune defect.

Test	Strength	Common limitation
Focused immune gene panel	High coverage, fast analysis, fewer unrelated findings	Misses genes outside the list
Exome sequencing	Broad coding-gene evaluation	Uneven coverage and limited noncoding detection
Genome sequencing	Broader structural and noncoding coverage	Interpretation burden and remaining technical blind spots
RNA or functional testing	Can show abnormal splicing or pathway function	Often specialized and tissue-dependent

Test selection should consider urgency. A rapid panel, exome, or genome may be appropriate in a critically ill infant because the result can guide transplant conditioning, donor choice, and avoidance of harmful therapies. In less urgent cases, phenotype-directed immune testing before sequencing can improve yield.

Ask whether the assay includes deletion and duplication analysis, mitochondrial genes when relevant, repeat or pseudogene-sensitive methods, mosaic detection, and reanalysis. Gene lists become outdated quickly in this field.

Sample collection and laboratory methods

Blood is commonly preferred because it usually provides high-quality DNA and allows parallel immune studies. Saliva or cheek swabs may be suitable for germline testing. No fasting is required, and most medicines do not change inherited DNA.

Several situations complicate the sample:

• Previous allogeneic stem cell transplant. Blood DNA may mainly reflect the donor. A skin fibroblast, hair-root, or other nonblood sample may be needed to test the recipient’s original germline.
• Somatic immune disease. Some disorders arise from variants present only in blood-cell subsets. Deep sequencing or sorted cells may be required.
• Clonal hematopoiesis or blood cancer. Acquired variants can be mistaken for germline findings in blood.
• Recent blood transfusion. Modern leukoreduced transfusions usually contribute little DNA, but the laboratory should know the history.
• Low-level mosaicism. Standard pipelines may filter a true variant if its allele fraction is low.

Panels usually use next-generation sequencing with bioinformatic analysis for single-nucleotide and small insertion/deletion variants. Read-depth or another method may detect exon deletions and duplications. Sanger sequencing, quantitative PCR, multiplex ligation-dependent probe amplification, chromosomal microarray, or long-read sequencing may confirm or extend findings.

Quality metrics matter. The report should list genes or exons with poor coverage, copy-number capability, mosaic detection threshold, and variant types not assessed. A negative result from a small older panel may warrant reanalysis or updated testing.

Functional tests can validate the pathway. Examples include oxidative burst testing for chronic granulomatous disease, protein expression by flow cytometry, lymphocyte proliferation, cytokine signaling, apoptosis assays, perforin expression, or complement function. Genetics and function often strengthen each other.

How to interpret the result

A pathogenic or likely pathogenic result can confirm a molecular diagnosis when the variant, inheritance, and phenotype align. The report should state the gene, DNA and protein change, zygosity, classification, and evidence.

Inheritance determines how many variants are needed. X-linked disorders may affect males with one pathogenic variant. Autosomal dominant disorders usually require one variant but can show incomplete penetrance. Autosomal recessive disorders usually require two pathogenic variants in trans. Some genes can cause different conditions through gain-of-function and loss-of-function variants, making mechanism important.

A variant of uncertain significance, or VUS, lacks enough evidence to classify. It is common on large panels. A VUS should not be assumed causal because rare benign variation is expected in everyone. Helpful evidence may include parental testing, segregation with disease, RNA analysis, protein expression, functional assays, population frequency, and future case reports.

A negative result means the assay found no reportable variant that explains the phenotype. It does not rule out an inborn error of immunity. Causes include an untested gene, undetectable structural or intronic variation, mosaicism, a phenocopy, incomplete scientific knowledge, or a nongenetic immune disorder.

A carrier result identifies one pathogenic variant in a recessive gene. Carriers are often healthy, though some genes have mild heterozygous effects. One variant may also mean a second variant was missed. The phenotype and gene-specific evidence guide follow-up.

An incidental or secondary finding may identify a medically actionable risk unrelated to the immune symptoms if exome or genome testing includes that option. Consent should address which findings will be returned.

The positive, negative, and uncertain genetic result must be integrated with the immune phenotype. A molecular result can be correct yet not explain every symptom, and a clinical immune diagnosis can remain valid without a molecular finding.

How a diagnosis can change care

A molecular diagnosis can alter care in several ways:

• selecting antimicrobial prophylaxis against the most likely pathogens;
• avoiding live vaccines in conditions where they may cause disease;
• deciding whether immunoglobulin replacement is appropriate;
• using targeted medicines such as abatacept for selected CTLA4/LRBA pathway disorders, JAK inhibitors for certain interferon or STAT gain-of-function disorders, or PI3K-delta inhibitors for activated PI3K-delta syndrome;
• monitoring for lymphoma, autoimmunity, lung disease, liver disease, or bowel inflammation;
• planning hematopoietic stem cell transplantation;
• choosing conditioning intensity and donor strategy;
• evaluating eligibility for gene therapy or a clinical trial;
• screening relatives before symptoms or before using them as stem cell donors.

Treatment depends on mechanism. A loss-of-function variant and a gain-of-function variant in the same gene may require opposite strategies. The gene name alone is not enough.

Some diagnoses affect transplant timing. Severe combined immunodeficiency, familial hemophagocytic lymphohistiocytosis, Wiskott-Aldrich syndrome, and selected combined immunodeficiencies may require early transplant. Other disorders are managed medically unless complications become severe.

Genetics can prevent harmful treatment. For example, an apparent autoimmune condition may actually reflect immune dysregulation that needs targeted therapy, while broad immunosuppression could worsen infection. Conversely, avoiding needed immune suppression because of infection fear can leave damaging inflammation uncontrolled.

Results can also guide surveillance. GATA2 deficiency may require monitoring for myelodysplasia, leukemia, viral disease, and pulmonary complications. DNA-repair disorders can alter chemotherapy and radiation sensitivity. Complement deficiencies change meningococcal prevention needs.

Care should remain individualized. People with the same variant can differ because of age, infections, modifier genes, treatment, and incomplete penetrance.

Inheritance and family testing

Once a pathogenic familial variant is known, targeted testing can identify relatives who are affected, at risk, or carriers. Testing should be paired with counseling because a healthy person may learn about future immune, autoimmune, or cancer risk.

In autosomal dominant inheritance, an affected person often has a 50% chance of passing the variant to each child. In autosomal recessive inheritance, when both parents carry a variant in the same gene, each pregnancy has a 25% chance of an affected child. X-linked inheritance creates different risks for sons and daughters depending on which parent carries the variant.

Penetrance may be incomplete. A parent who appears healthy can carry the same dominant variant as a severely affected child. Skewed X-chromosome inactivation can cause symptoms in some female carriers of X-linked disorders.

Family testing can improve safety in transplantation. A relative who carries the disease-causing variant may be an unsuitable stem cell donor even if they appear healthy and match the patient’s HLA. The transplant team should know the molecular diagnosis before final donor selection.

Reproductive options may include prenatal diagnosis, preimplantation genetic testing, donor gametes, or natural conception with postnatal testing. These are personal choices and require a confirmed pathogenic variant, not a VUS.

A negative family test is reassuring only for the tested familial variant. It does not rule out every immune disorder or unrelated genetic risk.

Next steps after a negative or uncertain result

Continue immune care based on the phenotype. Infection prevention, immunoglobulin replacement, inflammatory treatment, and monitoring should not be stopped simply because sequencing was negative.

Review whether the original panel was broad enough and whether it included copy-number analysis. Ask about poor-coverage regions, mosaic sensitivity, and the date of the gene list. Reanalysis after one to three years can identify newly recognized genes or reclassified variants.

For a VUS, do not test healthy relatives for prediction unless genetics professionals recommend segregation studies. Functional testing may be more informative. Ask the laboratory about its reclassification policy and keep contact details current.

For a strongly suggestive but negative case, options include trio exome, genome sequencing, RNA sequencing, long-read methods, chromosomal testing, or research enrollment. Phenocopies such as anti-cytokine autoantibodies and acquired somatic mutations may require specialized blood tests rather than germline sequencing.

Seek urgent medical care for severe infection, breathing difficulty, sepsis symptoms, uncontrolled bleeding, confusion, or rapid deterioration. Families of children with known serious immune defects should follow their emergency and fever plan.

Genetic counseling can organize the result, inheritance, testing of relatives, and future reanalysis. The best interpretation often comes from a team that includes clinical immunology, medical genetics, infectious disease, hematology, transplant specialists, and the molecular laboratory.

Building a useful immune phenotype

Genetic interpretation improves when the referral includes precise immune data. “Frequent infections” is less useful than a list of organisms, infection sites, ages, culture results, imaging, antibiotic duration, and complications. Pneumococcal sinus disease suggests a different pathway from disseminated mycobacteria, invasive Aspergillus, chronic norovirus, or severe herpesvirus disease.

Baseline testing commonly includes a complete blood count with differential, quantitative IgG, IgA, and IgM, lymphocyte subsets, and review of vaccine responses. Depending on the pattern, clinicians may add oxidative burst, complement screening, lymphocyte proliferation, switched-memory B cells, T-cell phenotyping, cytokine signaling, or pathogen-specific studies.

Results should be interpreted using age-adjusted ranges, especially in infants and children. A lymphocyte count normal for an adult may be dangerously low for a young infant. Immunoglobulin values also change with age and can be influenced by protein loss, medicines, and replacement therapy.

When acquired findings mimic inherited disease

Not every primary-looking immune disorder is germline. Anti–interferon-gamma autoantibodies can cause disseminated nontuberculous mycobacterial infection in adults. Anti–GM-CSF antibodies can cause pulmonary alveolar proteinosis and infection susceptibility. Somatic variants in immune cells can cause autoimmune lymphoproliferative or autoinflammatory phenotypes.

These phenocopies may not appear on a standard germline panel. The specialist may order anti-cytokine antibody assays, deep sequencing of sorted blood cells, bone marrow studies, or testing from more than one tissue. A negative saliva panel does not exclude a blood-limited somatic disorder.

Secondary causes remain common. Rituximab, corticosteroids, chemotherapy, anticonvulsants, nephrotic protein loss, intestinal lymphangiectasia, HIV, leukemia, and malnutrition can alter immune tests. Establishing the timing of symptoms relative to these exposures prevents incorrect genetic attribution.

Preparing for result disclosure

Families should know that a broad panel may produce more than one finding. A pathogenic variant can explain the main immune phenotype, while a carrier result or secondary finding may have separate implications. The report may also identify a VUS in a biologically plausible gene that remains unproven.

Bring a three-generation family history and, when possible, records from deceased or affected relatives. Testing parents can rapidly clarify whether a variant is new, inherited, or located in trans with another variant. In some disorders, an apparently unaffected parent needs immune testing because penetrance is incomplete.

A molecular diagnosis can be emotionally complex. It may end a long search but introduce concerns about siblings, children, cancer risk, or transplant. Genetic counseling should include what is known, what remains uncertain, which relatives are offered testing, and what support is available.

A result can also affect routine preventive care. Vaccine choices, household exposure advice, dental care, travel planning, and fever instructions may change according to the immune defect. These recommendations should be individualized; excessive isolation can harm schooling, work, and quality of life without adding protection.

References

• Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee 2025 (Consensus)
• The 2024 update of IUIS phenotypic classification of human inborn errors of immunity 2025 (Consensus)
• Current genetic diagnostics in inborn errors of immunity 2024 (Review)
• Consensus of the Italian Primary Immunodeficiency Network on the use and interpretation of genetic testing for diagnosing inborn errors of immunity 2025 (Consensus)
• Genomic Testing for Inborn Errors of Immunity 2025 (Guideline)
• Inborn errors of immunity (primary immunodeficiencies) 2025 (Review)

Disclaimer

This article provides general information and cannot diagnose or exclude an inborn error of immunity. Genetic findings must be interpreted with immune-function testing, infection history, examination, and specialist care. Infants or adults with severe infection, profound lymphopenia, sepsis symptoms, or rapid deterioration need urgent medical evaluation rather than waiting for a genetic result.