Congenital Defects of Phagocytes Panel

About Congenital Defects of Phagocytes

Congenital defects of phagocytes are characterized by reduced neutrophil counts or abnormal neutrophil function, leading to susceptibility to infections at epithelial surfaces and early infection dissemination^1,2. Chronic granulomatous disease (CGD) is the most prevalent form of congenital defects of phagocytes, affecting approximately 1 in 200,000 births in the United States³. CGD is characterized by recurrent bacterial and fungal infections, particularly involving Staphylococcus aureus, Pseudomonas species, Candida albicans, Aspergillus species, Nocardia species, pneumonia, granuloma formation, and failure to thrive⁴. Severe congenital neutropenia (SCN) represents another major category of congenital defects of phagocytes, defined by absolute neutrophil counts consistently below 500/µL and early-onset severe bacterial infections⁵. Some forms of neutropenia are associated with increased risk of developing myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML) due to G-CSF treatment^6,7.

These disorders can be inherited in autosomal dominant, autosomal recessive, or X-linked patterns, with some cases arising de novo. Several genes have been associated with CGD, including CYBB, CYBA, NCF1, NCF2, and NCF4⁴. For SCN, ELANE variants are most commonly identified, and additional genes including G6PC3, GFI1, HAX1, SBDS, and WAS have also been reported⁸. Causative variants include both sequence variants and copy number alterations. The diagnostic yield of this panel will vary based on the clinical phenotype, however it is estimated that approximately 60% for individuals with SCN and up to 80% of patients with CGD will receive a molecular diagnosis^4,8.

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

Due to the complexity of the region, the NCF1 gene is not analyzed as a result of the presence of pseudogenes.

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.