Severe Combined Immunodeficiency (SCID) Panel

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 broad classification of SCID may be subdivided based on B cell status and further subdivided based on NK cell status, which may provide insight into the causative genetic defect (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). Diagnoses are typically made via utilization of flow cytometry-based testing and newborn screening (NBS) assessment of T cell receptor excision circles (TRECs), however 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). Prior to NBS, population-based screening was the only method to identify those at risk for SCID prior to the onset of symptoms, however >80% of cases lack a positive family history (Chan and Puck. 2005. PubMed ID: 15696101; Chan et al. 2011. PubMed ID: 21035402; Kwan et al. 2014. PubMed ID: 25138334). The recurrence risk and prognosis may vary depending on the underlying genetics cause of the deficiency. In general, the prognosis is poor if there is a delay is 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).

The four main categories of SCID, based upon which immune cells are defective (T, B, and/or NK cells), each have distinct genetic causes. This panel focuses on genetic causes of T cell negative SCID that have been identified through literature, OMIM, and HGMD searches.

To date, there are 17 genes in which pathogenic variants have been described as causative for T cell negative SCID (Bousfiha et al. 2018. PubMed ID: 29226301; Picard et al. 2018. PubMed ID: 29226302; Tangye et al. 2020. PubMed ID: 31953710). The pattern of inheritance for SCID may be X-linked or autosomal recessive. X-linked SCID caused by IL2RG pathogenic variants accounts 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). All other genes in this panel show autosomal recessive inheritance. Adenosine deaminase deficiency due to variants in ADA contributes to ~15-20% of SCID cases (Allenspach et al. 1993. PubMed ID: 20301584; Kalman et al. 2004. PubMed ID: 14726805). 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). Pathogenic variants in AK2, CD247, CD3D, CD3E, CORO1A, DCLRE1C (ARTEMIS), IL2RG, JAK3, LAT, LIG4, NHEJ1, PRKDC, PTPRC, RAG1, and RAG2 together are responsible for ~10% of SCID (Allenspach et al. 1993. PubMed ID: 20301584; Kalman et al. 2004. PubMed ID: 14726805; Chan et al. 2011. PubMed ID: 21035402). Anywhere from ~13-31% of cases of SCID are idiopathic (Chan et al. 2011. PubMed ID: 21035402; Kwan et al. 2014. PubMed ID: 25138334).

Reported pathogenic variants in the causative genes include missense, nonsense, frameshift, splice site, and hypomorphic variants. Large copy number events have also been reported in the causative genes for T cell negative SCID. The frequency of the specific variants is dependent on the underlying genetic cause of disease. Pathogenic variants may be inherited or de novo. Of note, a founder variant in DCLRE1C [c.597C>A (p.Tyr199*)] has been identified in the Navajo Native American population (Li et al. 2002. PubMed ID: 12055248; Kwan et al. 2014. PubMed ID: 25138334). De novo variants may occur in ~50% of cases of X-linked SCID due to IL2RG pathogenic variants (Allenspach et al. 1993. PubMed ID: 20301584). Germline mosaicism has also been reported in cases of X-linked SCID among the Navajo Native American population (O'Marcaigh et al. 1997. PubMed ID: 9049783).

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

This test covers the common genetic causes of T cell negative SCID (Bousfiha et al. 2018. PubMed ID: 29226301; Picard et al. 2018. PubMed ID: 29226302; Tangye et al. 2020. PubMed ID: 31953710). The clinical sensitivity may vary depending on the B and NK cell status of the patient. While the exact clinical sensitivity of this grouping of genes is difficult to estimate, previous studies suggest that 58-87% of individuals with characteristic features of T cell negative SCID are expected to have a pathogenic variant identified in one of the genes on this panel (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).

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 reads.

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