CIBSS - Centre for integrative Biological Signalling Studies CIBSS

Beyond genotype: challenges in predicting disease risk for carriers of biallelic perforin variants

Wegehaupt O, Borisov O, Sieni E, Oyen F, Mann J, Coniglio ML, Chinnici A PhD, Pegoraro F, Beneforti L, Gilmour KC, Moshous D, de Saint Basile G, Zhang W, Marsh RA, De Fusco C, Wustrau K, Timeus F, Micalizzi C, Gunsilius E, Hosking L, Choo S, Ghosh S, Köttgen A, Lehmberg K, Ehl S.

Blood. 2025 Mar 16; doi: 10.1182/blood.2024027954. Online ahead of print.

Genetic screening for severe immunological diseases, like FHL2 due to PRF1 variants, offers potential for early intervention. However, variable penetrance of frequent hypomorphic genotypes such as A91V/pLOF complicates disease prediction. Functional assays do not reliably predict clinical outcome.