Table 4.
Additional variants of uncertain significance (VUS) and incidental copy number variations (CNVs).
| Gene | Variant | Type |
|---|---|---|
| ALG12 | Gene gain | CNV (duplication) |
| C8A | c.1450C>T (p.Arg484Cys) | Missense |
| CA5A | Gene gain | CNV |
| CD19 | c.1469G>A (p.Arg490Gln) | Missense |
| CTSF | c.215C>T (p.Ala72Val) | Missense |
| GAN | c.581A>T (p.Tyr194Phe) | Missense |
| HERC1 | c.10964C>A (p.Ser3655Tyr) | Missense |
| HERC1 | c.3715A>G (p.Ser1239Gly) | Missense |
| HNRNPU | c.1453G>A (p.Val485Ile) | Missense |
| LRBA | c.4547G>A (p.Arg1516Lys) | Missense |
| MLC1 | Ganancia (copia completa) | CNV |
| NDUFA12 | c.398_400del (p.Lys133del) | Delection in-frame |
| POLG | c.3445G>A (p.Ala1149Thr) | Missense |
To ensure diagnostic transparency and a comprehensive genomic overview, Table 5 documents co-occurring genetic alterations identified by the 1415-gene next-generation sequencing panel. All identified variants were rigorously evaluated and filtered in accordance with the standard joint consensus recommendations of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, alongside comprehensive genotype-phenotype correlation. Notably, despite the presence of variants in key immune-related loci such as LRBA and CD19, the patient’s acute hyperinflammatory clinical presentation, specialized flow cytometry lymphocyte subpopulation patterns, and bone marrow findings did not align with the disease phenotypes typically driven by pathogenic mutations in these genes. Consequently, under the ACMG/AMP framework, these alterations were classified as benign incidental findings or passenger VUS, validating the hemizygous pathogenic variant in XIAP/BIRC4 as the definitive and primary pathophysiological driver of XLP-2 and secondary hemophagocytic lymphohistiocytosis (HLH) in this infant.