Severe Combined Immunodeficiency/Omenn Syndrome via the IL7R Gene

Severe combined immunodeficiency (SCID) encompasses a diverse group of rare, life-threatening disorders. 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). SCID is caused by genetic defects that inhibit lymphocyte development and function, resulting in no T cell differentiation and abnormal development of B and natural killer (NK) lymphocytes (Fischer. 2000. PubMed ID: 11091267; Kumrah et al. 2020. PubMed ID: 32181275). The clinical features associated with SCID include recurrent and severe bacterial, viral, and fungal infections that begin in infancy (Fischer. 2000. PubMed ID: 11091267; Kwan et al. 2014. PubMed ID: 25138334; Kumrah et al. 2020. PubMed ID: 32181275). To date, there are over 20 genes known to be associated with SCID (Allenspach et al. 1993. PubMed ID: 20301584; Bousfiha et al. 2018. PubMed ID: 29226301; Picard et al. 2018. PubMed ID: 29226302; Kumrah et al. 2020. PubMed ID: 32181275; Tangye et al. 2020. PubMed ID: 31953710). The majority of the genes are involved in autosomal recessive SCID; however IL2RG is associated with an X-linked form of the disease (Allenspach et al. 1993. PubMed ID: 20301584).

Patients with SCID due to pathogenic variants in the IL7R gene lack T cells, but retain B cell and NK cell levels (T-B+NK+ SCID; Bousfiha et al. 2018. PubMed ID: 29226301). Previous studies have shown that IL7R variants are causative for 5-10% of all cases of SCID (Allenspach et al. 1993. PubMed ID: 20301584; Kalman et al. 2004. PubMed ID: 14726805; 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).

Classification of SCID may be subdivided based on B cell status and further subdivided based on NK cell status (Allenspach et al. 1993. PubMed ID: 20301584; Kumrah et al. 2020. PubMed ID: 32181275). Omenn Syndrome (OS), also known as leaky SCID, typically presents during the first year of life and is characterized by erythroderma, desquamation, eosinophilia, failure to thrive, lymphadenopathy and chronic diarrhea (Ege et al. 2005. PubMed ID: 15731174). Patients with OS have limited B cells and elevated T cell levels with impaired function resulting in a distinct inflammatory phenotype (T+B-NK+ SCID). OS is due to hypomorphic variants predominantly in the RAG1 and RAG2 genes, but DCLRE1C and IL7R can also have causative variants (Villa et al. 2002. PubMed ID: 11908269; Ege et al. 2005. PubMed ID: 15731174; Zago et al. 2014. PubMed ID: 24759676).

Regardless of the type of SCID, 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 SCID (Kwan et al. 2014. PubMed ID: 25138334).

To date, there are over 20 genes causative for autosomal recessive forms of SCID, including IL7R (Allenspach et al. 1993. PubMed ID: 20301584; Bousfiha et al. 2018. PubMed ID: 29226301; Picard et al. 2018. PubMed ID: 29226302; Kumrah et al. 2020. PubMed ID: 32181275; Tangye et al. 2020. PubMed ID: 31953710). Variants in IL2RG are causative for X-linked SCID and account for ~40-60% of all cases of SCID (Allenspach et al. 1993. PubMed ID: 20301584; Fischer. 2000. PubMed ID: 11091267; Chan et al. 2011. PubMed ID: 21035402). Pathogenic ariants in IL7R make up ~5-10% of all SCID cases (Allenspach et al. 1993. PubMed ID: 20301584; Kalman et al. 2004. PubMed ID: 14726805; Chan et al. 2011. PubMed ID: 21035402). OS is also inherited in an autosomal recessive manner through variants in the RAG1, RAG2, DCLRE1C, or IL7R genes (Villa et al. 2002. PubMed ID: 11908269; Ege et al. 2005. PubMed ID: 15731174; Zago et al. 2014. PubMed ID: 24759676).

Causative variants in SCID 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.

Variants in IL7R may lead to a range of clinical features, including classic SCID with autoimmunity and Omenn syndrome or leaky SCID (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 splice site leading to premature termination of the protein (Butte et al. 2007. PubMed ID: 17827065). No gross deletions or duplications have been reported to date in the IL7R gene (Human Gene Mutation Database). Hypomorphic variants in IL7R, typically missense, leading to impaired but not complete loss of protein function are associated with OS (Zago et al. 2014. PubMed ID: 24759676).

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 promoting T and NK cell survival (Puel and Leonard. 2000. PubMed ID: 10899029). A deficiency, either complete or partial, of the IL7R protein may interfere with T cell maturation and subsequent lymphoid cell development, resulting in the various forms of SCID (Kumrah et al. 2020. PubMed ID: 32181275).

Mouse models have been utilized to study the pathogenicity of variants in the IL7R gene. Several models of IL7R deficient models have been created and have shown severe impairment of B and T cell lymphopoiesis (Peschon et al. 1994. PubMed ID: 7964471; Maki et al. 1996. PubMed ID: 8692964). These models further elucidate the role of IL7R and its importance in the proliferation and maturation of lymphocytes.

Variants in IL7R make up 5-10% of all SCID cases (Allenspach et al. 1993. PubMed ID: 20301584; Kalman et al. 2004. PubMed ID: 14726805; Chan et al. 2011. PubMed ID: 21035402). For patients with a known T-B+NK+ immunophenotype or clinical features of OS, clinical sensitivity is greatly improved.

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

This test provides full coverage of all coding exons of the IL7R gene 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 full 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).

Testing will also cover 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).