Beyond genotype: challenges in predicting disease risk for carriers of biallelic perforin variants
Abstract
Abstract Genetic screening for severe congenital immunohematological diseases offers potential for early intervention, particularly through preemptive allogeneic hematopoietic stem cell transplantation (HSCT). However, the clinical value of such screening depends on precise prognostic predictions based on genotype-phenotype correlations and/or functional confirmation. We investigated familial hemophagocytic lymphohistiocytosis type 2 (FHL2), caused by PRF1 variants. Specifically, we evaluated the clinical significance of the frequent PRF1 A91V variant, if present in trans with a predicted loss-of-function (pLOF) PRF1 variant, defined as “disease mutation” listed in the Human Gene Mutation Database. We combined clinical and functional data from our hemophagocytic lymphohistiocytosis (HLH)–network registry with UK Biobank data to evaluate disease penetrance and clinical outcomes. Among 52 individuals with A91V/pLOF genotype in the registry, 39 (72%) showed FHL2-related manifestations with mean onset at 20 years. Four patients had recurrent disease, 15 received transplantation, and 14 died. Among 14 individuals with A91V/pLOF genotype identified by family screening (mean age, 29 years), however, only 1 was symptomatic. Moreover, among 21 A91V/pLOF carriers identified in 200 000 UK Biobank participants, 12 with genotypes identical to symptomatic registry patients, none had developed HLH by age 73 years. Premature stop pLOF alleles appeared more penetrant than missense variants, but functional data including perforin expression or cytotoxicity failed to predict disease manifestation. Our combined registry and population-based approach reveals significant variability in disease penetrance and severity among PRF1 A91V/pLOF carriers, with no clear association between genotype, functional data, and clinical outcomes. This complexity illustrates the challenges of genetic screening and highlights the need for careful clinical decision-making regarding preemptive HSCT in asymptomatic carriers.
Article Details
Authors (25)
Oliver Wegehaupt
1Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Oleg Borisov
3Institute of Genetic Epidemiology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Elena Sieni
8Azienda Ospedaliera Universitaria Meyer, Firenze, Italy
Florian Oyen
5Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Jasmin Mann
1Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Maria Luisa Coniglio
4Pediatric Hematology Oncology, Meyer Children’s Hospital IRCCS, Florence, Italy
Aurora Chinnici
4Pediatric Hematology Oncology, Meyer Children’s Hospital IRCCS, Florence, Italy
Francesco Pegoraro
2Department of experimental and clinical medicine, Florence, Italy
Linda Beneforti
4Pediatric Hematology Oncology, Meyer Children’s Hospital IRCCS, Florence, Italy
Kimberly Gilmour
Great Ormond Street Hospital for Children NHS Trust, London
Despina Moshous
8Université Paris Cité, Pediatric Hematology-Immunology and Rheumatology Department, Necker-Enfants Malades Hospital, Paris, France, Paris, France
Geneviève de Saint Basile
9Imagine Institute, Université de Paris Cité, INSERM U1163, Paris, France
Wenying Zhang
State Key Laboratory of Rare Earth Resource Utilization
Rebecca Marsh
11Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH
Carmela De Fusco
14Department of Oncology, Hematology, and Cell Therapy, AORN Santobono Pausilipon, Naples, Italy
Katharina Wustrau
14Department of pediatrics, University Medical Center Ulm, Ulm, Germany, Ulm, Germany
Fabio Timeus
16Pediatrics Department, Chivasso Hospital, Turin, Italy
Concetta Micalizzi
18Pediatric Hematology Oncology, IRCCS Istituto Giannina Gaslini, Genoa, Italy
Eberhard Gunsilius
19Department of Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria
Laine Hosking
20Department of Allergy and Immunology, The Royal Children's Hospital, Melbourne, VIC, Australia
Sharon Choo
20Department of Allergy and Immunology, The Royal Children's Hospital, Melbourne, VIC, Australia
Sujal Ghosh
21Department of Pediatric Oncology, Hematology, and Clinical Immunology, Center of Child and Adolescent Health, Heinrich Heine University, Duesseldorf, Germany
Anna Köttgen
Kai Lehmberg
5Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Stephan Ehl
1Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany