Immune Dysregulation Panel

About Immune Dysregulation Disorders

Diseases of immune dysregulation are disorders that affect the mechanisms that control the regulation of immune responses and immunological tolerance¹. These disorders encompass over 40 conditions categorized into subgroups by the International Union of Immunological Societies, including familial hemophagocytic lymphohistiocytosis (FHL) and autoimmune lymphoproliferative syndrome (ALPS)². FHL is characterized by excessive cytokine release and organ invasion by activated lymphocytes and macrophages, leading to fever, hepatosplenomegaly, coagulopathy, pancytopenia, hemophagocytosis, and hyperferritinemia^3,4. Without treatment, FHL can be fatal within months due to multiorgan failure. ALPS typically presents in early childhood with lymphadenopathy and hepatosplenomegaly, followed by autoimmune complications in the second decade^5,6.

Most FHL cases are attributed to variants in six genes, with PRF1, UNC13D, STX11, and STXBP2 being inherited in an autosomal recessive manner, while XIAP and SH2D1A are X-linked disorders⁷. The majority of ALPS cases (~70%) are inherited in an autosomal dominant manner due to variants in the FAS gene, while variants in the FASLG and CASP10 genes as reported in ~<1-6% of cases^8,9. Due to the genetic heterogeneity of immune dysregulation disorders, the diagnostic yield of this panel is difficult to estimate and varies based on the specific disorder.

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

This test does include analysis of a known pathogenic inversion in the UNC13D gene that occurs between a region in intron 30 and a region downstream of the UNC13D gene. This inversion involves exons 31 and 32 and has been reported previously in patients with FHL3 to abolish UNC13D protein expression (Meeths et al. 2011. PubMed ID: 21931115; Qian et al. 2014. PubMed ID: 24470399).

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.