Hyper IgE Syndrome Panel

Hyper-IgE Syndrome (HIES), also known as Job’s syndrome and Buckley’s syndrome, is characterized by a triad of symptoms including recurrent staphylococcal abscesses, recurrent airway infections, and increased immunoglobin E (>2000 U/ml) in serum (Szczawinska-Poplonyk et al., 2011. PMID: 22085750). HIES presents during childhood and with variable expressivity. There are both autosomal dominant (AD-HIES) and recessive forms (AR-HIES) of the disorder. AD-HIES affects about 1 in 100,000 people with patients being more prone to candidiasis, cyst forming pneumonia, connective tissue and skeletal abnormalities, retained primary teeth, and hyper-extensibility in joints. AR-HIES is distinguished from AD-HIES by increased occurrence and severity of viral infections such as Herpes simplex, Herpes zoster, and Molluscum contagiosum. AR-HIES patients are also more susceptible to food allergies, hemolytic anemia, vasculitis, and have a higher frequency of neurological complications including encephalitis, and vascular brain lesions. Connective and bone abnormalities are typically not observed in AR-HIES (Szczawinska-Poplonyk et al., 2011. PMID: 22085750).

TYK2 deficiency is very rare, only reported in two families, with patients presenting with HIES-like symptoms (Kilic et al., 2012).

Netherton Syndrome, which affects about 1 in 200,000 newborns, has similar skin features and elevated IgE levels to AD-HIES. These patients also present with fragile hair, ichthyosis linearis circumflexa, and failure to thrive (Sprecher et al., 2001. PMID: 11511292).

Genetic testing is helpful in the differential diagnosis of HIES subtypes and from other similar disorders including Omenn Syndrome, common variable immunodeficiency, atopic dermatitis, chronic granulomatous disease, and aspergillosis.

AD-HIES is completely penetrant and caused by pathogenic variants in the STAT3 gene with de novo pathogenic variants being frequently found. The autosomal recessive form (AR-HIES) is phenotypically similar, but due to pathogenic variants in the DOCK8 or PGM3 genes (Szczawinska-Poplonyk et al., 2011. PMID: 22085750; Sassi et al., 2014. PubMed ID: 24698316).

Netherton Syndrome and TYK2 deficiency are inherited in an autosomal recessive manner through pathogenic variants in the SPINK5 and TYK2 genes respectively (Kilic et al., 2012. PMID: 22402565; Sprecher et al., 2001. PMID: 11511292; Bitoun et al., 2002. PMID: 11841556).

AD-HIES represents 60-70% of all HIES cases with many being due to sporadic pathogenic variants. See individual gene test descriptions for information on molecular biology of gene products.

Pathogenic variants in the STAT3 gene are identified in 60% of cases of Autosomal Dominant Hyper IgE Syndrome. Analytical sensitivity is >95% by Sanger sequencing (Schimke et al. 2010. PMID: 20816194). In a study of 60 families with 82 patients with Autosomal Recessive Hyper IgE Syndrome (AR-HIES), pathogenic variants in the DOCK8 gene were found in 78% of cases. Of those patients, gross deletions ranging from a single exon to the whole gene were found in 32 of 64 patients (Engelhardt et al. 2015., PMID: 25724123). Analytical sensitivity is therefore about ~50% for detection of pathogenic variants in the DOCK8 gene as deletions encompassing one or more exon are not generally detected by sequencing. SPINK5 analytical sensitivity is >95% as gross deletions in the SPINK5 gene have only been reported in one case (Hachem et al., 2006. PMID: 16601670). In two separate studies of patients with confirmed Netherton Syndrome diagnosis, pathogenic variants in the SPINK5 gene were found in 14 of 19, and 21 of 21 individuals respectively (Sprecher et al., 2001. PMID: 11511292; Bitoun et al., 2002. PMID: 11841556).

In a study of 60 families with 82 patients with AR-HIES, pathogenic variants in the DOCK8 gene were found in 78% of cases. Of those patients, gross deletions ranging from a single exon to the whole gene were found in 32 of 64 patients (Engelhardt et al., 2015). Analytical sensitivity is therefore about ~50% for detection of pathogenic variants in the DOCK8 gene. Gross deletions in the STAT3 and SPINK5 genes have only been reported in a few cases (Schimke et. al., 2010. PMID: 20816194; Hachem et al., 2006. PMID: 16601670). A deletion encompassing the PGM3, UBE3D, ME1, and SNAP91 genes has been reported in a patient with immunodeficiency and skeletal dysplasia (Stray-Pedersen et al., 2014. PubMed ID: 24931394).

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

This panel provides 100% 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).

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).