Complement Deficiencies Panel

About Complement Deficiencies

Complement deficiencies are rare primary immunodeficiencies affecting approximately 0.03% of the general population and accounting for about approximately 5% of reported primary immunodeficiencies¹. The complement system, which mediates bacterial killing, can be activated through three pathways: classical, alternative, and lectin^2,3. Deficiencies in these pathways lead to distinct clinical presentations. Classical pathway deficiencies result in impaired clearance of immune complexes and debris, often leading to systemic lupus erythematosus (SLE)^2,3. Alternative pathway deficiencies typically present with recurrent pyogenic infections, particularly meningitis^2,3. Lectin pathway deficiencies may contribute to early childhood infections, though their clinical significance remains controversial^2,3. Age of symptom onset may be variable, but patients frequently present with increased susceptibility to infections caused by encapsulated organisms and autoimmune diseases – particularly SLE and hyperactivation^1,4. Most complement deficiencies follow an autosomal recessive inheritance pattern, with notable exceptions including X-linked properdin deficiency via the CFP gene and autosomal dominant variants in C1R or C1S (C1r or C1s periodontal Ehlers-Danlos), C3 (C3 gain of function), SERPING1 (C1 inhibitor deficiency), CFB (factor B gain of function), THBD (thrombomodulin deficiency), and CD46 [membrane cofactor protein (CD46) deficiency]^1,3,5. Causative variants can include both sequence variants and copy number variations. The diagnostic yield of this panel varies greatly based on the clinical presentation and age of onset for the affected individual¹.

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

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.