Test Id : HIESG

Skin biopsy or cultured fibroblast specimens:

For skin biopsy or cultured fibroblast specimens, fibroblast culture will be performed at an additional charge. If viable cells are not obtained, the client will be notified.

Cord blood:

For cord blood specimens that have an accompanying maternal blood specimen, maternal cell contamination studies will be performed at an additional charge.

Upon request and after initial testing is complete, WESPR / Panel to Whole Exome Sequencing Reflex Test, Varies may be added to this test. To obtain more information about this option or add WESPR testing, call 800-533-1710.

Customization of this panel and single gene analysis for any gene present on this panel are available. For more information see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies. To modify this panel via CGPH, use the Inborn Errors of Immunity/Bone Marrow Failure/Telomeropathy/Pulmonary Fibrosis/Very Early Onset IBD/Pancreatitis disease state for step 1 on the Custom Gene Ordering Tool.

Targeted testing for familial variants (also called site-specific or known variants testing) is available for the genes on this panel. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about testing option, call 800-533-1710.

Patient Preparation: A previous hematopoietic stem cell transplant from an allogenic donor will interfere with testing. For information about testing patients who have received a hematopoietic stem cell transplant, call 800-533-1710.

Submit only 1 of the following specimens:

Specimen Type: Whole blood

Container/Tube: Lavender top (EDTA) or yellow top (ACD)

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send whole blood specimen in original tube. Do not aliquot.

3. Whole blood collected postnatal from an umbilical cord is also acceptable. See Additional Information

Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 4 days/Frozen 4 days

Additional Information:

1. Specimens are preferred to be received within 4 days of collection. Extraction will be attempted for specimens received after 4 days, and DNA yield will be evaluated to determine if testing may proceed.

2. To ensure minimum volume and concentration of DNA are met, the requested volume must be submitted. Testing may be canceled if DNA requirements are inadequate.

3. For postnatal umbilical cord whole blood specimens, maternal cell contamination studies are recommended to ensure test results reflect that of the patient tested.  A maternal blood specimen is required to complete maternal cell contamination studies. Order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on both the cord blood and maternal blood specimens under separate order numbers.

Specimen Type: Saliva

Patient Preparation: Patient should not eat, drink, smoke, or chew gum 30 minutes prior to collection.

Supplies:

DNA Saliva Kit High Yield (T1007)

Saliva Swab Collection Kit (T786)

Container/Tube:

Preferred: High-yield DNA saliva kit

Acceptable: Saliva swab

Specimen Volume: 1 Tube if using T1007 or 2 swabs if using T786

Collection Instructions: Collect and send specimen per kit instructions.

Specimen Stability Information: Ambient (preferred) 30 days/Refrigerated 30 days

Additional Information: Saliva specimens are acceptable but not recommended. Due to lower quantity/quality of DNA yielded from saliva, some aspects of the test may not perform as well as DNA extracted from a whole blood sample. When applicable, specific gene regions that were unable to be interrogated will be noted in the report. Alternatively, additional specimen may be required to complete testing.

Specimen Type: Blood spot

Supplies: Card-Blood Spot Collection (Filter Paper) (T493)

Container/Tube:

Preferred: Collection card (Whatman Protein Saver 903 Paper)

Acceptable: PerkinElmer 226 filter paper or blood spot collection card

Specimen Volume: 2 to 5 Blood spots

Collection Instructions:

1. An alternative blood collection option for a patient older than 1 year is a fingerstick. For detailed instructions, see How to Collect a Dried Blood Spot Sample.

2. Let blood dry on the filter paper at ambient temperature in a horizontal position for a minimum of 3 hours.

3. Do not expose specimen to heat or direct sunlight.

4. Do not stack wet specimens.

5. Keep specimen dry.

Specimen Stability Information: Ambient (preferred)/Refrigerated

Additional Information:

1. Blood spot specimens are acceptable but not recommended. Multiple extractions will be required to obtain sufficient yield for supplemental analysis, and there is significant risk for test failure due to insufficient DNA.

2. Due to lower concentration of DNA yielded from blood spot, some aspects of the test may not perform as well as DNA extracted from a whole blood sample. When applicable, specific gene regions that were unable to be interrogated will be noted in the report. Alternatively, additional specimen may be required to complete testing.

3. For collection instructions, see Blood Spot Collection Instructions

4. For collection instructions in Spanish, see Blood Spot Collection Card-Spanish Instructions (T777)

5. For collection instructions in Chinese, see Blood Spot Collection Card-Chinese Instructions (T800)

Specimen Type: Skin biopsy

Supplies: Fibroblast Biopsy Transport Media (T115)

Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin.

Specimen Volume: 4-mm Punch

Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours

Additional Information:

1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.

2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks are required to culture fibroblasts before genetic testing can occur.

Specimen Type: Cultured fibroblasts

Source: Skin or tissue

Container/Tube: T-25 flask

Specimen Volume: 2 Flasks

Collection Instructions: Submit confluent cultured fibroblast cells from a skin or tissue biopsy. Cultured cells from a prenatal specimen will not be accepted.

Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours

Additional Information:

1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.

2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks are required to culture fibroblasts before genetic testing can occur.

Specimen Type: Extracted DNA

Container/Tube:

Preferred: Screw Cap Micro Tube, 2 mL with skirted conical base

Acceptable: Matrix tube, 1 mL

Collection Instructions:

1. The preferred volume is at least 100 mcL at a concentration of 75 ng/mcL.

2. Include concentration and volume on tube.

Specimen Stability Information: Frozen (preferred) 1 year/Ambient/Refrigerated

Additional Information: DNA must be extracted in a CLIA-certified laboratory or equivalent and must be extracted from a specimen type listed as acceptable for this test (including applicable anticoagulants). Our laboratory has experience with Chemagic, Puregene, Autopure, MagnaPure, and EZ1 extraction platforms and cannot guarantee that all extraction methods are compatible with this test. If testing fails, one repeat will be attempted, and if unsuccessful, the test will be reported as failed and a charge will be applied. If applicable, specific gene regions that were unable to be interrogated due to DNA quality will be noted in the report.

• Informed Consent for Genetic Testing
• Informed Consent for Genetic Testing (Spanish)
• Targeted Genes and Methodology Details for Hyper-IgE Syndrome Gene Panel
• Inborn Errors of Immunity, Autoimmunity, and Autoinflammatory Disease Patient Information

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing (Spanish) (T826)

2. Molecular Genetics: Congenital Inherited Diseases Patient Information (T521)

3. Inborn Errors of Immunity, Autoimmunity, and Autoinflammatory Disease Patient Information

See Specimen Required

Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of hyper-IgE syndrome (HIES)

Establishing a diagnosis of HIES, allowing for appropriate management and surveillance for disease features based on the gene and/or variant involved

Identifying variants within genes known to be associated with HIES, allowing for predictive testing of at-risk family members and/or determination of targeted management (anticipatory guidance, management changes, specific therapies)

This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 21 genes associated with hyper-IgE syndrome: AIRE, CARD11, CARD9, CARMIL2, DOCK8, ERBIN, IL6R, IL6ST, IL17RA, IL17RC, IL17F, PGM3, SPINK5, STAT1, STAT3, TGFBR1, TGFBR2, TRAF3IP2, TYK2, WAS, and ZNF341. See Targeted Genes and Methodology Details for Hyper-IgE Syndrome Gene Panel and Method Description for additional details.

Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, recurrence risk assessment, familial screening, and genetic counseling for hyper-IgE syndrome.

Skin biopsy or cultured fibroblast specimens:

For skin biopsy or cultured fibroblast specimens, fibroblast culture will be performed at an additional charge. If viable cells are not obtained, the client will be notified.

Cord blood:

For cord blood specimens that have an accompanying maternal blood specimen, maternal cell contamination studies will be performed at an additional charge.

Hyper IgE syndrome (HIES) is characterized by an increased susceptibility to infection (particularly recurrent skin and pulmonary infections), eczema, and elevated serum IgE. There is variable expression among individuals and additional features may be present, including vascular, skeletal, and connective tissue pathology. While the incidence of HIES is estimated to be between 1:100,000 to 1,000,000 at birth, this may be an underestimate due to incomplete penetrance.

Dominant negative variants in STAT3 were first identified as the genetic cause of HIES, which was referred to as Job syndrome. Now additional genes have been identified, and cases due to STAT3 variants are referred to as STAT3-HIES. Infection in STAT3-HIES is often due to Staphylococcus aureus and Candida species. While HIES may be inherited in an autosomal dominant pattern, many cases are de novo.

Genetic variants in additional genes have been identified that result in HIES. ZNF341 (zinc finger protein 341) deficiency results in an autosomal recessive form of HIES, also known as AR-HIES. Partial deficiency of interleukin (IL) 6 signal transducer (IL6ST) has been reported in both autosomal recessive and autosomal dominant forms of HIES, while complete IL6ST deficiency is typically fatal in utero or early in the neonatal period. Additionally, variants in PGM3, CARD11, and other genes have been identified as causes of HIES. Furthermore, other distinct immunodeficiency disorders or other conditions may have overlapping features with HIES (eg, elevated IgE or severe infection), making the diagnosis challenging. While the phenotypes of disorders leading to elevated IgE and predisposition to infection are often similar, the therapeutic options and treatment strategies differ.

An interpretive report will be provided

All detected variants are evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

1. Richards S, Aziz N, Bale S, et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424

2. Tsilifis C, Freeman AF, Gennery AR. STAT3 Hyper-IgE syndrome-an update and unanswered questions. J Clin Immunol. 2021;41(5):864-880

3. Asano T, Khourieh J, Zhang P, et al. Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance. J Exp Med. 2021;218(8):e20202592. doi:10.1084/jem.20202592

4. Hsu AP, Davis J, Puck JM, Holland SM, Freeman AF. STAT3 hyper IgE syndrome. In: Adam MP, Everman DB, Mirzaa GM, et al, eds. GeneReviews.[Internet] University of Washington, Seattle; 2010. Updated March 26, 2020. Accessed November 18, 2025. Available at www.ncbi.nlm.nih.gov/books/NBK25507/

5. Tangye SG, Al-Herz W, Bousfiha A, et al. Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42(7):1473-1507. doi:10.1007/s10875-022-01289-3

Next-generation sequencing (NGS) and/or Sanger sequencing are performed to test for the presence of variants in coding regions and intron/exon boundaries of the genes analyzed, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for deletions/insertions (delins) less than 40 base pairs (bp), and above 95% for deletions up to 75 bp and insertions up to 47 bp. NGS and/or a polymerase chain reaction-based quantitative method is performed to test for the presence of deletions and duplications in the genes analyzed.

Varies

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This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

81443

88233- Tissue culture, skin, solid tissue biopsy (if appropriate)

88240- Cryopreservation (if appropriate)