Cohort of A91V/pLOF cases. Schematic illustration of the perforin gene with its functional domains. On the right side, the variants are indicated that were observed in trans with the A91V variant. Variants in red cause HLH in homozygosity (pLOF/pLOF), “pLOF” in brown cause HLH in compound heterozygosity (pLOF1/pLOF2), pLOF marked in black have not been linked to FHL2-associated phenotypes in the literature. Each line represents the longitudinal course of 1 individual with A91V/pLOF genotype in years of life. The patient identification number is indicated. Right part: cases identified by genetic analysis of symptomatic patients. Left part: cases identified by family screening. Red circle: episode of systemic HLH or HLH-like inflammation. Purple circle: neuroinflammatory symptoms, either isolated or as part of systemic HLH. Green circle: lymphoma. Pink circle: recurrent febrile episodes not meeting HLH criteria. Gray star: HSCT. Black vertical line: age at last clinical information. †patient deceased. Connected lines with a junction point symbolize individuals belonging to the same family. Brackets pointing to variants summarize groups of patients carrying this A91V/pLOF genotype.