Staff Scientist National Institutes of Health Bethesda, Maryland, United States
Background/Case Studies: CD59 is a GPI-anchored glycoprotein on the surface of many cell types. It inhibits the assembly of the membrane attack complex, thereby preventing complement-mediated cell lysis. A lack of functional CD59 protein has been linked to chronic hemolysis and immune-related neuropathies. Recent large-scale whole-genome and whole-exome sequencing projects are generating vast datasets of human variation across globally diverse and genetically heterogeneous populations. We aimed to conduct a comprehensive analysis of CD59 gene variants from publicly available genome databases and to explore whether computational analysis could distinguish neutral variants from deleterious variants.
Study
Design/Methods: Variants in the CD59 coding sequence of exons 4, 5, and 6 and their splice sites were systematically compiled from 4 major populations — African, Caucasian, Asian, and Latin American — and across 6 whole-genome and whole-exome databases, including All of Us, The IndiGenomes database, The GenomeAsia 100K Project, the 1000 Genomes Project, and the South Asian Genomes and Exomes database. Our search was supplemented by reviewing reference lists from original research and review articles. The ClinVar database was also queried for pathogenic CD59 variants. The PredictSNP metaserver was used to assess the functional impact of non-synonymous single nucleotide variants (SNVs). The accuracy of in silico prediction for non-synonymous SNVs was validated by comparing the predicted effects with clinically reported outcomes in published studies.
Results/Findings: Among 488,592 individuals, 160 distinct variants were identified in 6,881 subjects (0.7%). Of 93 non-synonymous variants, 43 were classified as deleterious and 49 (2 variants encoded the same amino acid change) as neutral by PredictSNP. Notably, the non-synonymous CD59 variants previously reported in patients were also classified as “deleterious” by the PredictSNP, with an accuracy of up to 87%. We identified 37 potentially deleterious CD59 variants, although these were extremely rare in the general population. Conclusions: In addition to their direct pathogenic effects, CD59 variants may contribute to unexplained hemolysis during ABO-incompatible platelet transfusions, which are generally considered safe. Reduced CD59 activity due to deleterious variants may be a contributing factor. Whole genome sequencing, combined with clinical monitoring, can help identify these variants, enabling personalized care and cascade screening of at-risk family members. We compiled CD59 variants classified as neutral or deleterious by PredictSNP from genome databases to support variant interpretation in clinical contexts.
