Abstract
BackgroundHemophagocytic lymphohistiocytosis (HLH) is a rapid-onset, potentially fatal hyperinflammatory syndrome. A prompt molecular diagnosis is crucial for appropriate clinical management. Here, we validated and prospectively evaluated a targeted high-throughput sequencing approach for HLH diagnostics.MethodsA high-throughput sequencing strategy of 12 genes linked to HLH was validated in 13 patients with previously identified HLH-associated mutations and prospectively evaluated in 58 HLH patients. Moreover, 2504 healthy individuals from the 1000 Genomes project were analyzed in silico for variants in the same genes.ResultsAnalyses revealed a mutation detection sensitivity of 97.3 %, an average coverage per gene of 98.0 %, and adequate coverage over 98.6 % of sites previously reported as mutated in these genes. In the prospective cohort, we achieved a diagnosis in 22 out of 58 patients (38 %). Genetically undiagnosed HLH patients had a later age at onset and manifested higher frequencies of known secondary HLH triggers. Rare, putatively pathogenic monoallelic variants were identified in nine patients. However, such monoallelic variants were not enriched compared with healthy individuals.ConclusionsWe have established a comprehensive high-throughput platform for genetic screening of patients with HLH. Almost all cases with reduced natural killer cell function received a diagnosis, but the majority of the prospective cases remain genetically unexplained, highlighting genetic heterogeneity and environmental impact within HLH. Moreover, in silico analyses of the genetic variation affecting HLH-related genes in the general population suggest caution with respect to interpreting causality between monoallelic mutations and HLH. A complete understanding of the genetic susceptibility to HLH thus requires further in-depth investigations, including genome sequencing and detailed immunological characterization.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0244-1) contains supplementary material, which is available to authorized users.
Highlights
Hemophagocytic lymphohistiocytosis (HLH) is a rapid-onset, potentially fatal hyperinflammatory syndrome
To interpret findings in patients without an established molecular diagnosis and provide an overview of genetic variations in genes linked to hemophagocytic lymphohistiocytosis (HLH), we examined the frequency of variants in genes included in our panel among 2504 unrelated individuals from the 1000 Genomes project
We have demonstrated the efficacy of a highthroughput sequencing approach for the molecular diagnosis of patients with suspected HLH
Summary
Hemophagocytic lymphohistiocytosis (HLH) is a rapid-onset, potentially fatal hyperinflammatory syndrome. A prompt molecular diagnosis is crucial for appropriate clinical management. We validated and prospectively evaluated a targeted high-throughput sequencing approach for HLH diagnostics. Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome that presents with unremitting fever, splenomegaly and cytopenia [1]. According to the HLH-2004 protocol, HLH can be defined as fulfillment of at least five of eight clinical and laboratory criteria [2]. Genetic, as well as secondary forms of HLH have been described. HLH is typically treated by immunosuppression, followed by hematopoietic stem cell transplantation in familial cases [1]. Current HLH criteria poorly discriminate underlying causes of disease. Therapies tailored to different etiologies of HLH may improve treatment outcome [3]
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