Omenn Syndrome Panel

Severe combined immunodeficiency (SCID) encompasses a diverse group of rare, life-threatening disorders. The broad classification of SCID may be subdivided based on T, B, and natural killer (NK) cell status (Allenspach et al. 1993. PubMed ID: 20301584; Kumrah et al. 2020. PubMed ID: 32181275). Omenn Syndrome (OS) is a form of SCID, also known as leaky SCID, which typically presents during the first year of life. OS is characterized by erythroderma, desquamation, alopecia, hepatosplenomegaly, eosinophilia, failure to thrive, lymphadenopathy, chronic diarrhea, and elevated serum IgE levels (Aleman et al. 2001. PubMed ID: 11795679; Ege et al. 2005. PubMed ID: 15731174). Patients with OS have significantly decreased levels of B cells and elevated levels of T cells with impaired function that results in the expression of a restricted T cell receptor (TCR) repertoire (Aleman et al. 2001. PubMed ID: 11795679; Ege et al. 2005. PubMed ID: 15731174). This leads to the distinct inflammatory phenotype seen in patients with OS (T+B-NK+ SCID).

While the true incidence of SCID is unknown, newborn screening studies suggest that 1 in 70,000 births are affected with a range of 1 in 40,000 to 100,000 (Fischer. 2000. PubMed ID: 11091267; Kwan et al. 2014. PubMed ID: 25138334; Kumrah et al. 2020. PubMed ID: 32181275). The exact incidence of Omenn syndrome is unknown; however, studies analyzing the causative genetic variants in patients with various types of SCID identified 0-8% of their SCID cohorts had OS (Lindegren et al. 2004. PubMed ID: 14724556; Sarzotti-Kelsoe et al. 2009. PubMed ID: 19433858; Chan et al. 2011. PubMed ID: 21035402). The specific causative genetic variants in the OS patients in these studies were not reported. OS is primarily due to variants in the RAG1 and RAG2 genes, but may also be caused by variants in the IL7R and DCLRE1C (ARTEMIS) genes (Villa et al. 2002. PubMed ID: 11908269; Ege et al. 2005. PubMed ID: 15731174; Zago et al. 2014. PubMed ID: 24759676). With variable T cell populations, the diagnosis of OS is often more difficult than classical SCID where T cells are nearly absent. Interestingly, patients with OS due to DCLRE1C variants have a heightened sensitivity to ionizing radiation and chemotherapeutic agents, which may distinguish these patients from those with OS due to RAG1, RAG2, or IL7R variants (Moshous et al. 2001. PubMed ID: 11336668; Ulus-Senguloglu et al. 2012. PubMed ID: 23093295).

It is necessary to establish a genetic diagnosis for genetic counseling, prognostication, and optimization of treatment (Kwan et al. 2014. PubMed ID: 25138334; Kumrah et al. 2020. PubMed ID: 32181275). The recurrence risk and prognosis may vary depending on the underlying genetic cause of the deficiency. In general, the prognosis is poor if there is a delay in diagnosis and therapy. Early hematopoietic stem cell transplantation (HSCT) is the most established treatment for patients with OS (Aleman et al. 2001. PubMed ID: 11795679; Kwan et al. 2014. PubMed ID: 25138334).

OS is inherited in an autosomal recessive manner through pathogenic variants in the RAG1, RAG2, DCLRE1C, and IL7R genes (Villa et al. 2002. PubMed ID: 11908269; Ege et al. 2005. PubMed ID: 15731174; Zago et al. 2014. PubMed ID: 24759676). Patients with more severe clinical features of SCID primarily have null variants in RAG1, RAG2, DCLRE1C, or IL7R. Patients with OS tend to have hypomorphic variants, typically missense, which lead to an impaired, but not complete, loss of protein function (Villa et al. 2002. PubMed ID: 11908269; Ege et al. 2005. PubMed ID: 15731174; Zago et al. 2014. PubMed ID: 24759676). Variants in these genes may be inherited from unaffected parents or may occur de novo in the patient. Studies analyzing newborns with SCID determined that only ~20% had a family history of immunodeficiency, while ~80% of cases lacked a positive family history (Chan and Puck. 2005. PubMed ID: 15696101; Puck. 2007. PubMed ID: 17931561; Chan et al. 2011. PubMed ID: 21035402; Kwan et al. 2014. PubMed ID: 25138334). Those with a lack of family history are a result of de novo variants and unknown carrier status. These studies analyzed SCID as a whole and did not break down the analysis into the different subtypes of SCID.

RAG1 and RAG2 are the most commonly involved genes with OS. Causative variants in RAG1 occur throughout the coding region and are mostly missense; however nonsense and small frameshift deletions and insertions have also been reported (Kalman et al. 2004. PubMed ID: 14726805). RAG2 SCID variants are often nonsense, frameshift, or small deletions leading to premature protein termination, while RAG2 variants in patients with OS are primarily missense or compound heterozygous for a missense and truncating variant (Corneo et al. 2001. PubMed ID: 11313270; Noordzij et al. 2002. PubMed ID: 12200379). Gross deletions of the RAG1 and RAG2 genes have rarely been reported (Schwarz et al. 1996. PubMed ID: 8810255; Kato et al. 2015. PubMed ID: 25739914). The RAG1 and RAG2 genes encode DNA recombinases that mediate VDJ recombination to facilitate B and T cell receptor assembly (Kumrah et al. 2020. PubMed ID: 32181275).

Variants in the DCLRE1C gene have been reported in patients with OS (Villa et al. 2002. PubMed ID: 11908269; Ege et al. 2005. PubMed ID: 15731174). Large deletions or nonsense variants are causative for ~50% of DCLRE1C mediated SCID, while missense, splicing, small deletions, and small insertions/duplications make up the other half of causative variants (Noordzij et al. 2003. PubMed ID: 12406985; Pannicke et al. 2010. PubMed ID: 19953608). Of note, a founder variant in DCLRE1C [c.597C>A (p.Tyr199*)] has been identified in the Native American population and is estimated to cause SCID in ~1 in 2,000 births (Allenspach et al. 1993. PubMed ID: 20301584; Li et al. 2002. PubMed ID: 12055248, Kalman et al. 2004. PubMed ID: 14726805; Kwan et al. 2014. PubMed ID: 25138334). The DCLRE1C gene encodes a DNA cross-link repair protein, commonly referred to as ARTEMIS, which mediates VDJ recombination to facilitate B and T cell receptor assembly (Kumrah et al. 2020. PubMed ID: 32181275).

Variants in the IL7R gene have been reported in patients with OS (Butte et al. 2007. PubMed ID: 17827065; Zago et al. 2014. PubMed ID: 24759676). Missense and nonsense variants, splice site alterations, and small deletions have all been reported as causative variants for SCID (Giliani et al. 2005. PubMed ID: 15661025). Of note, a deep intronic variant in the IL7R gene, c.379+288G>A, also causes SCID through generation of a cryptic slice site leading to premature termination of the protein (Butte et al. 2007. PubMed ID: 17827065). No gross deletions or duplications have been reported in the IL7R gene (Human Gene Mutation Database). The IL7R gene encodes a component of the Interleukin 7 receptor that binds the cytokine IL7. IL7 signaling stimulates T-cell maturation by promoting differentiation of hematopoietic stem cells into lymphoid progenitors, proliferation of B-cells during maturation, and T and NK cell survival (Puel and Leonard. 2000. PubMed ID: 10899029).

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

This test covers the known genetic causes of OS (Villa et al. 2002. PubMed ID: 11908269; Ege et al. 2005. PubMed ID: 15731174; Zago et al. 2014. PubMed ID: 24759676). The clinical sensitivity may vary depending on the immunophenotype of the patient. The incidence of OS is rare as compared to SCID, therefore the exact clinical sensitivity of this grouping of genes in relation to OS is difficult to estimate. Previous analyses of the causative genetic variants in patients with various types of SCID determined that 0-8% of their SCID cohorts had OS (Lindegren et al. 2004. PubMed ID: 14724556; Sarzotti-Kelsoe et al. 2009. PubMed ID: 19433858; Chan et al. 2011. PubMed ID: 21035402). However, the specific genetic variants were not reported.

Overall, pathogenic variants in RAG1 were identified in ~5-15% of all cases of SCID, while RAG2 pathogenic variants were identified in ~1.9-8%, IL7R pathogenic variants were identified in ~5-10%, and DCLRE1C pathogenic variants were identified in ~1% (outside of the Native American population) (Allenspach et al. 1993. PubMed ID: 20301584; Kalman et al. 2004. PubMed ID: 14726803; Lindegren et al. 2004. PubMed ID: 14724556; Sarzotti-Kelsoe et al. 2009. PubMed ID: 19433858; Chan et al. 2011. PubMed ID: 21035402; Dvorak et al. 2013. PubMed ID: 23818196; Kwan et al. 2014. PubMed ID: 25138334).

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).

Of note, our test covers the deep intronic variant (c.379+288G>A) in the IL7R gene (Butte et al. 2007. PubMed ID: 17827065).

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).