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

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.

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Journal
Blood
Published
2025-03-16
DOI
https://doi.org/10.1182/blood.2024027954
Citations
4
Primary Topic
Autoimmune and Inflammatory Disorders Research
Type
article
Field-Weighted Citation Impact
7.08
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article

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

Oliver Wegehaupt, Maria Luisa Coniglio, Francesco Pegoraro, Laine Hosking et al.
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Beyond genotype: challenges in predicting disease risk for carriers of biallelic perforin variants

Oliver Wegehaupt, Maria Luisa Coniglio, Francesco Pegoraro, Laine Hosking, Jasmin Mann, Linda Beneforti, Despina Moshous, Rebecca Marsh, Stephan Ehl, Geneviève de Saint Basile, Kai Lehmberg, Eberhard Gunsilius, Aurora Chinnici, Fabio Timeus, Florian Oyen, Carmela Fusco, Katharina Wustrau, Concetta Micalizzi, Elena Sieni, Anna Köttgen, Kimberly Gilmour, Oleg Borisov, Wenying Zhang, Sujal Ghosh, Sharon Choo
article en
4 citations

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.

BloodVol. 145(25)
Cincinnati Children's Hospital Medical Center (US), Hôpital Necker-Enfants Malades (FR), Royal Children's Hospital (AU), BJC HealthCare (US), Innsbruck Medical University (AT), Inserm (FR), Universität Hamburg (DE), University of Freiburg (DE), Universität Ulm (DE), Université Paris Cité (FR), Great Ormond Street Hospital (GB), University Medical Center Freiburg (DE), Istituto Giannina Gaslini (IT), CTO Hospital (IT), Düsseldorf University Hospital (DE), Sorbonne Paris Cité (FR), University Medical Center Hamburg-Eppendorf (DE), Meyer Children's Hospital (IT), Santobono Children's Hospital (IT), Ospedale Regina Margherita (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University Hospital Ulm (DE), Immune Deficiency Foundation (US), Heinrich Heine University Düsseldorf (DE), University of Florence (IT), University College London (GB), University of Cincinnati Medical Center (US)
Peace, Justice and strong institutions
Openalex Percentile: Top 3%
Autoimmune and Inflammatory Disorders Research
7.08
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