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Effective Immunological Guidance of Genetic Analyses Including Exome Sequencing in Patients Evaluated for Hemophagocytic Lymphohistiocytosis

Ammann, Sandra, Lehmberg, Kai, zur Stadt, Udo, Klemann, Christian, Bode, Sebastian F. N., Speckmann, Carsten, Janka, Gritta, Wustrau, Katharina, Rakhmanov, Mirzokhid, Fuchs, Ilka, Hennies, Hans C. and Ehl, Stephan (2017) Effective Immunological Guidance of Genetic Analyses Including Exome Sequencing in Patients Evaluated for Hemophagocytic Lymphohistiocytosis. Journal of Clinical Immunology. ISSN 0271-9142

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Abstract

We report our experience in using flow cytometry-based immunological screening prospectively as a decision tool for the use of genetic studies in the diagnostic approach to patients with hemophagocytic lymphohistiocytosis (HLH). We restricted genetic analysis largely to patients with abnormal immunological screening, but included whole exome sequencing (WES) for those with normal findings upon Sanger sequencing. Among 290 children with suspected HLH analyzed between 2010 and 2014 (including 17 affected, but asymptomatic siblings), 87/162 patients with "full" HLH and 79/111 patients with "incomplete/atypical" HLH had normal immunological screening results. In 10 patients, degranulation could not be tested. Among the 166 patients with normal screening, genetic analysis was not performed in 107 (all with uneventful follow-up), while 154 single gene tests by Sanger sequencing in the remaining 59 patients only identified a single atypical CHS patient. Flow cytometry correctly predicted all 29 patients with FHL-2, XLP1 or 2. Among 85 patients with defective NK degranulation (including 13 asymptomatic siblings), 70 were Sanger sequenced resulting in a genetic diagnosis in 55 (79%). Eight patients underwent WES, revealing mutations in two known and one unknown cytotoxicity genes and one metabolic disease. FHL3 was the most frequent genetic diagnosis. Immunological screening provided an excellent decision tool for the need and depth of genetic analysis of HLH patients and provided functionally relevant information for rapid patient classification, contributing to a significant reduction in the time from diagnosis to transplantation in recent years.

Item Type: Article
Uncontrolled Keywords: Hemophagocytic lymphohistocytosis; Diagnosis; Flow cytometry; Degranulation; Whole exome sequencing
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RJ Pediatrics
Schools: School of Applied Sciences
Related URLs:
Depositing User: Hans Hennies
Date Deposited: 02 Oct 2017 08:46
Last Modified: 13 Oct 2017 09:43
URI: http://eprints.hud.ac.uk/id/eprint/33508

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