Severe Combined Immunodeficiency (SCID) Region of Interest - Trio or Proband Only

Test Background

The Severe Combined Immunodeficiency (SCID) Region of Interest Analysis was designed in collaboration with leading experts in pediatric immunology.

This Region of Interest (ROI) study covers 59 genes, therefore providing a highly comprehensive SCID sequencing assessment. The SCID Region of Interest Report includes orthogonally-confirmed variants identified by Next Generation Sequencing and the results of the companion deletion/duplication analysis, if ordered.

This study can be ordered for the proband alone by submitting a sample from the affected individual or as a trio with parental samples included in the analysis.

In the case of a non-diagnostic finding, ordering providers have the option to go beyond the Region of Interest test by ordering an expansion to the Claritas Clinical Exome (Test Code N0527). A new sample will not need to be submitted. Interpretation will be provided in a new report that will be available in 12-14 weeks. 

Clinical Features and Causes of SCID

Severe Combined Immune Deficiency (SCID) leads to life-threatening infections unless the immune system can be restored through a bone marrow transplant, enzyme replacement, or gene therapy. Infants with SCID who lack a family history have been diagnosed in the past only after developing serious infections. Early identification of SCID through screening of all newborns can allow for life-saving intervention before infections occur. Currently, several states have adopted the T-cell receptor excision circle (TREC) assay as part of their routine newborn screening programs. TREC screening has identified infants with most forms of SCID and also some infants with very low T-lymphocytes due to other conditions.

A list of several of these disorders follows, although there may be additional syndromes that qualify for inclusion as combined immunodeficiency (CID) that are not listed. These disorders include: Bare Lymphocyte syndrome (MHC class-II deficiency); purine nucleoside phosphorylase (PNP) deficiency; ZAP70 deficiency; CD25 deficiency; Cartilage-Hair Hypoplasia; Coronin 1A deficiency, and MHC class I deficiency. Sometimes a child with clinical CID is found to have a mutation in a gene (listed previously under Other Causes of SCID) that would be expected to result in SCID, but does not have the typically severe disease as anticipated. This situation is often called “leaky” SCID.

Severe combined immunodeficiency (SCID) can be caused by mutations in a variety of genes. Although the clinical presentation can vary depending on which gene carries a mutation, there are several common characteristics observed throughout the different forms of SCID. Patients will typically present in infancy with severe, persistent infections of bacterial, viral, fungal, and/or protozoal origin. In addition, these individuals have poor wound healing and failure to thrive. In states where newborn screening includes the TREC test for poor maturation of T cells, presymptomatic infants may be identified. T-cell lymphopenia is common to almost all forms of SCID, while the presence/absence of B-cells and NK-cells varies and can be used to help determine appropriate genetic testing. The prevalence of SCID in the general population is approximately 1/50,000 live births, with males showing a higher prevalence as the most common form of SCID is X-linked. There are also forms of SCID that are autosomal recessive.

Test Characteristics

  • Assessment of 59 genes related to SCID; protein coding sequences and 10 bp of adjacent intronic sequences are analyzed
  • Deep intronic variants (20 total) that have been classified as “Pathogenic” or “Likely Pathogenic” are also sequenced and analyzed. Table 1 below provides the list of non-coding regions and deep intronic variants.
  • Orthogonal approach using Illumina NextSeq™ with simultaneous confirmation of 95% of variants on the Thermo Fisher (formerly Life Technologies) Ion Proton™; reported variants that are not orthogonally confirmed are confirmed by Sanger sequencing
  • Mean coverage of >100x for the combined Illumina NextSeq™ and Thermo Fisher Ion Proton™ platforms; >98% at 20x**
  • This assay can detect SNVs, insertions, and deletions less than 10 bp
  • Exon 11 of the CORO1A gene cannot be sequenced with current sequencing methods due to repeat sequences elsewhere in the genome.
  • Adding the companion deletion/duplication analysis (Test Code C0959) can increase detection rate for copy number variants and larger indels.

**Data for the Claritas Clinical Exome

Indications for Testing

  • Severe infections during infancy
  • Defective immune cells – T lymphocytes, B lymphocytes, or Natural killer (NK) cells
  • Other symptoms include
    • Growth delay
    • Failure to thrive
    • Hypotonia
    • Rashes
    • Diarrhea

Increase the Power of the Assay

  • Add companion deletion/duplication testing (Test Code C0959)
  • If no diagnostic findings are reported in the ROI, providers can order an expanded interpretation of the whole clinical exome (Test Code N0527)

Additional Service Highlights

  1. Providers may request a review of variant classification at any time.
  2. Providers may access the Interpretative Genomics Service at Boston Children’s Hospital, which provides consultation with experts in genes and/or phenotypes. Please contact MedicalDirector@claritasgenomics.com for more information.
  3. Claritas Genomics will release raw data files or provide access to exome data via NextCODE to authorized health care providers. Review Data Return Program details here.

Deep Intronic Variants

Table 1:

Gene Intronic Variant
ADA c.976-34G>A
ADA c.1079-15T>A
ATM c.1236-404C>T
ATM c.2639-384A>G
ATM c.3403-12T>A
ATM c.3994-159A>G
ATM c.4612-12A>G
ATM c.5763-1050A>G
CHD7 c.2836-15C>G
CHD7 c.5405-17G>A
DCLRE1C c.973-1777G>C
DOCK8 c.742-15T>G
DOCK8 c.742-18C>G
IL2RG c.*308A>G
IL2RG c.270-15A>G
IL7R c.379+288G>A
PNP c.286-18G>A
TTC7A c.1510+105T>A
ZAP70 c.838-80G>A
ZAP70 c.1624-11G>A

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Genes

ADA, AK2, ATM, B2M, BCL10, CARD11, CD247, CD3D, CD3E, CD3G, CD8A, CHD7, CIITA*, CORO1A, CTPS1, DCLRE1C, DOCK2, DOCK8, FOXN1, GATA2, IKBKB, IKZF1, IL21R, IL2RG, IL7R, JAK3, LCK, LIG4, MAGT1, MALT1, MAP3K14, NHEJ1*, ORAI1, PIK3CD, PNP, PRKDC, PTPRC, RAC2, RAG1, RAG2, RFX5, RFXANK, RFXAP, RHOH, RMRP, SH2D1A, SMARCAL1, SP110, STIM1, STK4, TAP1, TAP2, TAPBP, TBX1, TNFRSF4, TPP2, TTC7A, UNC119, ZAP70

*Deletion/duplication analysis for this gene is not included or coverage is limited

About Claritas

Claritas Genomics serves children affected with complex genetic disorders by providing timely and accurate results, resolving families’ long search for answers. By combining clinical expertise of the world’s best pediatric specialists with innovative platform solutions, Claritas is working to improve patient care and enable new discoveries. We are committed to the highest quality and accessibility of information and our interpretive services and unique approach to reporting set the standard for reliably and clearly communicating genetic information.

Now is the time to integrate genomics into clinical practice to inform, guide and improve medical treatment for kids around the world.