B-Negative SCID Panel
Severe combined immunodeficiency, SCID, X-SCID SCID B cell-negative, SCID NK cell-negative
Severe combined immunodeficiency (SCID) is a group of rare monogenic primary immunodeficiency disorders characterized by a block in T lymphocyte differentiation 1.
Clinical presentation is fairly uniform and is characterized by early onset of infections, mainly of the respiratory tract and gut. Patients will typically present in infancy with severe, persistent infections of bacterial, viral, fungal and/or protozoal origin 1, 2. In addition, these individuals have poor wound healing and failure to thrive. The most frequent infections observed in SCID patients include oral candidiasis, persistent diarrhea with growth impairment and/or interstitial pneumonitis. The persistence and recurrence of infections in SCID patients rapidly leads to growth impairment and malnutrition.
SCIDs are classified according to immunological phenotype into SCID with absence of T cells but presence of B cells (B-positive SCID) or SCID with absence of both (B-negative SCID) 3. About 20% of patients with SCID have a phenotype characterized by an absence of mature T and B lymphocytes, while functional natural killer cells are detectable. Usually the thymus is hypoplastic and the condition can be cured by allogeneic bone marrow transplantation 3.
Several genes (ADA, AK2, DCLRE1C, LIG4, NHEJ1, RAC2, RAG1, and RAG2) are associated with B-negative SCID 4.
With an incidence of 1 in 200,000 live births, ADA deficiency accounts for approximately one-third of all cases of autosomal recessive SCID and approximately 15% of all cases of SCID 5. ADA deficiency is caused by homozygous or compound heterozygous pathogenic variants in the ADA gene. Pathogenic variants in either the RAG1 or RAG2 genes account for ~4% of cases of SCID 5. Pathogenic variants in the AK2 gene, missense, nonsense, splice site and small deletions, account for ~8%-12% of SCID cases 1, 5. Pathogenic variants in the LIG4, NHEJ1, DCLRE1C and RAC2 genes are less common, but they have been reported in several familial cases of B-negative SCID 1, 5.
Infections are treated with specific antibiotic, antifungal, and antiviral agents and administration of intravenous immunoglobulin (IVIg); prophylaxis is provided for Pneumocystis jiroveci infection. Immune reconstitution by bone marrow transplantation or gene replacement therapy is required for survival, thus an early diagnosis enables early immune reconstitution and prevents severe complications.
CENTOGENE offers sequencing and deletion/duplication analysis of genes in the B-negative SCID panel (ADA, AK2, DCLRE1C, LIG4, NHEJ1, RAC2, RAG1, RAG2).
The differential diagnosis of B-negative SCID includes the following diseases - depending on the major presenting symptoms:
- Lymphoproliferative disorders
- Wiskott-Aldrich syndrome
- Hyperimmunoglobulinemia E syndrome
- Lymphohistiocytosis (hemophagocytic lymphohistiocytosis).
CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free Whole Genome Sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for B-negative SCID using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the B-negative SCID panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no clinically relevant variant is identified after analysis of the B-negative SCID panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.
The following individuals are candidates for B-negative SCID gene testing:
- Individuals with a family history of B-negative SCID and presentation of the most common symptoms
- Individuals without a positive family history, but with symptoms resembling B-negative SCID
- Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).
Sequencing, deletion/duplication of B-negative SCID related genes should be performed in all individuals suspected of having this condition. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of pathogenic variants, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of B-negative SCID, identify at-risk family members, provide information about reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.