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Severe Combined Immunodeficiency/Omenn Syndrome via the RAG1 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
7287 RAG1 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7287RAG181479 81479(x2) $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Megan Piazza, PhD, FACMG

Clinical Features and Genetics

Clinical Features

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 RAG1 gene lack T and B cells while retaining normal NK cell levels (T-B-NK+ SCID; Bousfiha et al. 2018. PubMed ID: 29226301). Previous studies have shown that RAG1 variants are causative for 5-15% of all cases of SCID (Lindegren et al. 2004. PubMed ID: 14724556; Sarzotti-Kelsoe et al. 2009. PubMed ID: 19433858; Chan et al. 2011. PubMed ID: 21035402; 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).

Genetics

To date, there are over 20 genes causative for autosomal recessive forms of SCID, including RAG1 (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. Variants in IL2RG, ADA, and IL7R account for ~75% 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 variants in RAG1 account for 5-15% of all cases of SICD (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; Kwan et al. 2014. PubMed ID: 25138334). 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.

Pathogenic variants in RAG1 may lead to a wide range of clinical features, including classic SCID with autoimmunity, hyper IgM syndrome, common variable immune deficiency, and Omenn syndrome or leaky SCID (Kumrah et al. 2020. PubMed ID: 32181275). Patients with more severe clinical features of SCID primarily have null variants in RAG1, while those with OS tend to have hypomorphic variants in RAG1, 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). RAG1 variants occur throughout the coding region and are rarely overlapping for SCID and OS (Villa et al. 2002. PubMed ID: 11908269). Overall, most causative variants in RAG1 are missense; however nonsense and small frameshift deletions and insertions have also been reported (Kalman et al. 2004. PubMed ID: 14726805). Gross deletions of the RAG1 gene have been reported in very rare cases (Schwarz et al. 1996. PubMed ID: 8810255; Kato et al. 2015. PubMed ID: 25739914).

The RAG1 gene encodes a DNA recombinase that works to initiate VDJ recombination to create variable immunoglobulin and T cell receptor rearrangements, which are required for B and T cell precursor survival (Kumrah et al. 2020. PubMed ID: 32181275). A deficiency, either complete or partial, of the RAG1 protein will alter VDJ recombination, which would promote the T cells to undergo apoptosis and result 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 RAG1 gene. Mouse models with homozygous deletions in Rag1 were found to not have any mature B or T lymphocytes due to an inability to initiate lymphocyte differentiation at an immature stage (Mombaerts et al. 1992. PubMed ID: 1547488). Overall, the loss of RAG1 function led to a SCID phenotype in the mice due to a similar mechanism as is seen in individuals with SCID. A similar phenotype has also been described for Rag2 deficient mouse models (Shinkai et al. 1992. PubMed ID: 1547487). Knockin mouse models have been created in which the endogenous Rag1 was replaced with Rag1 carrying hypomorphic variants. These models had impaired lymphocyte development and decreased VDJ rearrangement and mimicked most of the symptoms of human Omen syndrome (Khiong et al. 2007. PubMed ID: 17476359; Giblin et al. 2009. PubMed ID: 19126872).

Clinical Sensitivity - Sequencing with CNV PG-Select

Pathogenic variants in RAG1 have been identified in 5-15% of patients presenting with various types of SCID (Lindegren et al. 2004. PubMed ID: 14724556; Sarzotti-Kelsoe et al. 2009. PubMed ID: 19433858; Chan et al. 2011. PubMed ID: 21035402; Kwan et al. 2014. PubMed ID: 25138334). For patients with a known T-B-NK+ immunophenotype or clinical features of OS, clinical sensitivity is improved.

Testing Strategy

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 RAG1 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels.

Indications for Test

Candidates for testing include those with severe lymphopenia and lack of adaptive immunity. Ideal candidates have a T-B-NK+ immunophenotype, which is consistent with SCID via RAG1, or clinical features indicating OS. Testing is especially recommended for newborns identified via newborn screening for SCID using T-cell receptor excision circles (TRECs) screening. Carrier testing is available for individuals with a family history of the disease and for the reproductive partners of individuals who carry pathogenic variants in RAG1.

Gene

Official Gene Symbol OMIM ID
RAG1 179615
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
Severe Combined Immunodeficiency (SCID) Panel

Citations

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
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