Tu165 - Beyond Monogenic Models: Genetic Influences on Immunodeficiency Penetrance in TACI Variant Carriers

Abstract Text: Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency (PID). While PIDs are generally considered monogenic diseases, fewer than 10% of CVID patients receive a monogenic diagnosis suggesting that many cases may not be monogenic in origin. The p.C104R and p.A181E variants in TACI, which regulates B cell number and function, are associated with CVID and found in approximately 7% of patients. However, as these variants are present in about 1% of healthy individuals, they cannot solely cause the disease. Why then, do some carriers of these TACI variants develop CVID, while others remain unaffected?

To investigate the role of additional genetic variants on the variable penetrance of immunodeficiency in individuals with TACI p.C104R and p.A181E, we analysed whole-genome sequencing data from 886 individuals with PID, including 51 carriers of TACI variants, and another 160 TACI variant carriers without PID. We assessed the burden of common variants (minor allele frequency [MAF] > 5%) using polygenic risk scores, and rarer variants (MAF < 3%) in digenic combinations using the supervised machine-learning approach Variant Combinations Pathogenicity Predictor.

Our analysis revealed that common genetic variation does not drive antibody deficiency in TACI variant carriers. However, we identified several candidate modifying variants within the underexplored 1-3% MAF range. Notably, some of these variants are predicted to be deleterious in genes essential for B cell function, such as TNFRSF13C (the BAFF receptor). This work highlights the role of non-Mendelian mechanisms in the genetic penetrance of TACI p.C104R and p.A181E and identifies potential novel modifiers.