Targeted high-throughput sequencing for genetic diagnostics of hemophagocytic lymphohistiocytosis

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dc.authorid0000-0003-3294-5394
dc.contributor.authorTesi, Bianca
dc.contributor.authorLagerstedt-Robinson, Kristina
dc.contributor.authorChiang, Samuel Cern Cher
dc.contributor.authorBdira, Eya Ben
dc.contributor.authorAbboud, Miguel Raul
dc.contributor.authorBelen, Burcu
dc.contributor.authorDevecio?lu, Ömer
dc.contributor.authorFadoo, Zehra
dc.contributor.authorYeoh, Eng Juh
dc.contributor.authorErichsen, Hans Christian
dc.contributor.authorMottonen, Merja
dc.contributor.authorAkar, Himmet Haluk
dc.contributor.authorHastbacka, Johanna
dc.contributor.authorKaya, Zühre
dc.contributor.authorNunes, Susana
dc.contributor.authorPatıroğlu, Türkan
dc.contributor.authorSabel, Magnus
dc.contributor.authorTu?rul Sarıbeyo?lu, Ebru
dc.contributor.authorTvedt, Tor Henrik Anderson
dc.contributor.authorÜnal, Ekrem
dc.contributor.authorÜnal, Şule
dc.contributor.authorÜnüvar, Ayşegül
dc.contributor.authorMeeths, Marie
dc.contributor.authorHenter, Jan Inge
dc.contributor.authorNordenskjold, Magnus
dc.contributor.authorBryceson, Yenan Troi
dc.date.accessioned10.07.201910:49:13
dc.date.accessioned2019-07-10T19:56:05Z
dc.date.available10.07.201910:49:13
dc.date.available2019-07-10T19:56:05Z
dc.date.issued2015
dc.departmentİstanbul Medipol Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Çocuk Sağlığı ve Hastalıkları Ana Bilim Dalı
dc.descriptionWOS: 000366702100002
dc.descriptionPubMed ID: 26684649
dc.description.abstractBackground: Hemophagocytic 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. Methods: A 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. Results: Analyses 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. Conclusions: We 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.
dc.description.sponsorshipEuropean Research Council under the European Union's Seventh Framework Programme (FP)/ERC [311335]; Swedish Research Council; Swedish Children's Cancer Foundation; Swedish Cancer Foundation; Swedish Foundation for Strategic Research; Wallenberg Foundation; Stockholm County Council (ALF project); Board of Postgraduate Studies at Karolinska Instituteten_US
dc.description.sponsorshipThe authors thank the physicians that referred the patients for genetic and immunological evaluations and Nina Jantti and Anh Nhi Tran for technical assistance. This study was supported by the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement no. 311335, Swedish Research Council, Swedish Children's Cancer Foundation, Swedish Cancer Foundation, Swedish Foundation for Strategic Research, Wallenberg Foundation and the Stockholm County Council (ALF project). B.T. was supported by a PhD student scholarship awarded by the Board of Postgraduate Studies at Karolinska Institutet.en_US
dc.identifier.citationTesi, B., Lagerstedt-Robinson, K., Chiang, S. C. C., Bdira, E. B., Abboud, M. R., Belen, B. ... Bryceson, Y. T. (2015). Targeted high-throughput sequencing for genetic diagnostics of hemophagocytic lymphohistiocytosis. Genome Medicine, 7. https://dx.doi.org/10.1186/s13073-015-0244-1
dc.identifier.doi10.1186/s13073-015-0244-1
dc.identifier.issn1756-994X
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://dx.doi.org/10.1186/s13073-015-0244-1
dc.identifier.urihttps://hdl.handle.net/20.500.12511/2567
dc.identifier.volume7
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherBioMed Central
dc.relation.ispartofGenome Medicineen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsAttribution 4.0 International*
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subjectHemophagocytic
dc.subjectlymphohistiocytosis
dc.subjectSequencing
dc.subjectGenetic
dc.titleTargeted high-throughput sequencing for genetic diagnostics of hemophagocytic lymphohistiocytosis
dc.typeArticle

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