Combined Immunodeficiencies with Syndromic Features Panel

About Combined Immunodeficiencies with Syndromic Features

Combined immunodeficiencies (CID) with syndromic features are disorders affecting the adaptive immune system that also involve multiple organ systems including ectodermal, skeletal, nervous, and gastrointestinal systems^1,2. These disorders can be classified into nine categories: congenital thrombocytopenia, DNA repair defects, thymic defects, immune-osseous dysplasia, hyper IgE syndromes, defects of vitamin B12 and folate metabolism, anhidrotic ectodermodysplasia with immunodeficiency, calcium channel defects, and other defects^3.4. While severe infections may be the first presentation, non-immune features can also be the initial symptoms^5,6. A study of over 16,000 patients from the European Society for Immunodeficiencies registry determined that approximately three-quarters of the patients presented with infections, while about 12% presented with syndromic features⁷. The most commonly diagnosed conditions were DiGeorge syndrome, ataxia telangiectasia, Wiskott-Aldrich syndrome, and hyper IgE syndrome⁷. Most syndromic CIDs follow autosomal recessive or autosomal dominant inheritance patterns, though X-linked inheritance and de novo variants also occur³. Causative variants can include both sequence variants and copy number alterations. Due to the genetic heterogeneity of these disorders, the diagnostic yield of this panel varies depending on the specific immunodeficiency and presenting features.

All genetic tests have limitations. Please refer to our Test Methods page for limitations relevant to this methodology.

Coverage for IKBKG is limited due to paralogy associated with the pseudogene, IKBKGP1. NGS is not able to cover exons 3-10, including the common 11.7 kb deletion (exons 4-10). 

The analytical sensitivity of the PGxome platform has been validated at >99% for single nucleotide variants, >95% for indels <49 bp, and >99% for CNV ≥3 exons in size. Sensitivity is reduced in regions with repetitive elements or paralogy.

The analytical sensitivity of the PGnome platform has been validated at >99% for sequence variants and >99% for structural variants (SV) 1kb-10Mb in size. Sensitivity is reduced in regions with repetitive elements or paralogy.

PGxome® platform: Capture and amplification based Next Generation Sequencing (NGS) is used to sequence the coding regions of nearly all genes and immediate flanking non-coding DNA (± 10 bp) in all available transcripts along with other non-coding regions harboring known disease-causing variants. Results are filtered to defined genes in panel. Reportable variants include both sequence variants and NGS-based detection of copy number variants (CNVs).

PGnome® platform: PCR-free Next Generation Sequencing (NGS) is used to sequence the coding regions of nearly all genes as well as intronic and intergenic regions. Detailed variant analysis and interpretation is focused on the coding exons and ± 10 bp into introns. Genomic variants outside of these coding regions are not investigated unless warranted (for example, if a gene of interest is highlighted by the provider, or if a single-hit pathogenic variant is found in a recessive gene). Results are filtered to defined genes in panel. Reportable variants include sequence variants; NGS-based detection of structural variants (SV), including copy number variants (CNVs) and inversions; and repeat expansion variants in currently available relevant genes.

Variants not meeting our quality threshold through NGS alone are confirmed with an orthogonal method, including but not limited to Sanger and array.

All variants within the analyzed genes which are classified as pathogenic, likely pathogenic, risk, or variant of uncertain significance will be reported.