| Title: | Beyond genotype: challenges in predicting disease risk for carriers of biallelic perforin variants |
| Journal: | Blood |
| Published: | 19 Jun 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40090000/ |
| DOI: | https://doi.org/10.1182/blood.2024027954 |
Publication 15583
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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.</p>
18 Keywords
- Adolescent
- Adult
- Aged
- Alleles
- Child
- Female
- Genetic Predisposition to Disease
- Genotype
- Hematopoietic Stem Cell Transplantation
- Heterozygote
- Humans
- Loss of Function Mutation
- Lymphohistiocytosis, Hemophagocytic
- Male
- Middle Aged
- Perforin
- Registries
- Young Adult
25 Authors
- Oliver Wegehaupt
- Oleg Borisov
- Elena Sieni
- Florian Oyen
- Jasmin Mann
- Maria Luisa Coniglio
- Aurora Chinnici
- Francesco Pegoraro
- Linda Beneforti
- Kimberly Gilmour
- Despina Moshous
- Geneviève de Saint Basile
- Wenying Zhang
- Rebecca Marsh
- Carmela De Fusco
- Katharina Wustrau
- Fabio Timeus
- Concetta Micalizzi
- Eberhard Gunsilius
- Laine Hosking
- Sharon Choo
- Sujal Ghosh
- Anna Köttgen
- Kai Lehmberg
- Stephan Ehl
1 Application
| Application ID | Title |
|---|---|
| 103789 | Use of UK Biobank data to support genetic studies of Mendelian and complex diseases with a focus on inborn errors of immunity |
Enabling scientific discoveries that improve human health