• Test code: 08113
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit

Invitae Hyper IgE Syndrome Panel

Test description

The Invitae Hyper IgE Syndrome Panel analyzes 4 genes which are associated with Hyper IgE syndromes. Analysis of these genes may confirm a diagnosis of Hyper IgE syndrome in individuals with newborn rash, eczema, boils, recurrent viral and fungal infections, pneumatoceles, elevated serum IgE, and eosinophilia. Identification of disease-causing variants provide accurate risk assessment and carrier status for at-risk relatives.

Order test

Primary panel (4 genes)

Alternative tests to consider

Consider the Invitae Monogenic Inflammatory Bowel Disease Panel or Invitae Autoinflammatory Syndromes Panel for patients with hyper IgE and eosinophilia.

Gene Disorder Protein name Protein symbol
DOCK8 DOCK8 deficiency dedicator of cytokinesis 8 DOCK8
STAT3 AD-HIES (Job or Buckley Syndrome), STAT3 GOF mutations signal transducer and activator of transcription 3 STAT3
SPINK5 Comel-Netherton syndrome lymphoepithelial kazal type related inhibitor LEKT1
PGM3 PGM3 deficiency phosphoglucomutase 3 PGM3

Hyper-IgE recurrent infection syndrome (HIES) is a primary immunodeficiency characterized by recurrent respiratory and skin infections, eczema, pneumatocele-forming pneumonias, elevated serum IgE level, and eosinophilia. The two subtypes of HIES, autosomal dominant HIES (AD-HIES) and autosomal recessive HIES (AR-HIES), have overlapping clinical presentations with several distinctions. AD-HIES, caused by pathogenic variants in the STAT3 gene, is also associated with mucocutaneous candidiasis, characteristic facial features, and connective tissue and skeletal abnormalities. Most affected individuals survive into adulthood, but lifespan is often shortened due to complications with cystic lung disease and recurrent pneumonia. Individuals with AR-HIES, associated with biallelic mutations in DOCK8, may experience low IgM, recurrent viral infections, autoimmunity, central nervous system complications, vascular disease and malignancies such as squamous-cell carcinomas and T-cell lymphoma. The complications of this condition can be life-threatening in childhood.

PGM3-CDG is a congenital disorder of glycosylation resulting in a primary immunodeficiency and neurologic syndrome which shares symptoms of Hyper IgE syndrome. Affected individuals exhibit clinical variability but commonly present with recurrent infections, neutropenia, leukopenia, dermatitis, vasculitis and non-progressive neurologic dysfunction including myoclonus, peripheral neuropathy, ataxia and cognitive impairment. Netherton syndrome, associated with biallelic mutations in SPINK5, is characterized by erythroderma, skin peeling, elevated IgE levels, and trichorrhexis invaginata (sparse, fragile bamboo-like hair). Other features of Netherton syndrome include environmental and food allergies, enteropathy, and failure to thrive.

Pathogenic variants in STAT3 are identified in >95% of individuals meeting clinical criteria for classic hyper IgE syndrome (AD-HIES). Biallelic mutations in DOCK8 are found in many, but not all, individuals with AR-HIES.

Hyper IgE syndromes may be inherited in an autosomal dominant or autosomal recessive pattern depending on the gene involved:

Gene Inheritance
DOCK8 Autosomal recessive
STAT3 Autosomal dominant
SPINK5 Autosomal recessive
PGM3 Autosomal recessive

AD-HIES, AR-HIES, and PGM3-CDG each have a prevalence of less than 1 in 1 milion. The prevalence of Netherton syndrome is 1-9 per million.

  1. Hsu, AP, et al. Autosomal Dominant Hyper IgE Syndrome. 2010 Feb 23. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301786
  2. Grimbacher, B, et al. Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder. N. Engl. J. Med. 1999; 340(9):692-702. PMID: 10053178
  3. Zhang, Q, et al. Combined immunodeficiency associated with DOCK8 mutations. N. Engl. J. Med. 2009; 361(21):2046-55. PMID: 19776401
  4. Renner, ED, et al. Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J. Pediatr. 2004; 144(1):93-9. PMID: 14722525
  5. Freeman, AF, et al. Causes of death in hyper-IgE syndrome. J. Allergy Clin. Immunol. 2007; 119(5):1234-40. PMID: 17335882
  6. Sassi, A, et al. Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels. J. Allergy Clin. Immunol. 2014; 133(5):1410-9, 1419.e1-13. PMID: 24698316
  7. Fleisher, TA. Autosomal Recessive Phosphoglucomutase 3 (PGM3) Mutations Link Glycosylation Defects to Atopy, Immune Deficiency, Autoimmunity, and Neurocognitive Impairment. Pediatrics. 2014; 134 Suppl 3:S181-2. PMID: 25363991
  8. Stray-Pedersen, A, et al. PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia. Am. J. Hum. Genet. 2014; 95(1):96-107. PMID: 24931394
  9. Zhang, Y, et al. Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment. J. Allergy Clin. Immunol. 2014; 133(5):1400-9, 1409.e1-5. PMID: 24589341
  10. Boskabadi, H, et al. Netherton syndrome, a case report and review of literature. Iran J Pediatr. 2013; 23(5):611-2. PMID: 24800031
  11. Grimbacher, B, et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am. J. Hum. Genet. 1999; 65(3):735-44. PMID: 10441580
  12. Woellner, C, et al. Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J. Allergy Clin. Immunol. 2010; 125(2):424-432.e8. PMID: 20159255

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

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.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
DOCK8 NM_203447.3
PGM3 NM_001199917.1
SPINK5 NM_006846.3
STAT3 NM_139276.2