Universität zu Köln

Ammann, Sandra ORCID: 0000-0003-0385-1890, Lehmberg, Kai, zur Stadt, Udo, Klemann, Christian ORCID: 0000-0002-5639-8690, Bode, Sebastian F. N., Speckmann, Carsten ORCID: 0000-0002-6217-1556, 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. J. Clin. Immunol., 37 (8). S. 770 - 781. NEW YORK: SPRINGER/PLENUM PUBLISHERS. ISSN 1573-2592

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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:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ammann, Sandra UNSPECIFIED orcid.org/0000-0003-0385-1890 UNSPECIFIED Lehmberg, Kai UNSPECIFIED UNSPECIFIED UNSPECIFIED zur Stadt, Udo UNSPECIFIED UNSPECIFIED UNSPECIFIED Klemann, Christian UNSPECIFIED orcid.org/0000-0002-5639-8690 UNSPECIFIED Bode, Sebastian F. N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Speckmann, Carsten UNSPECIFIED orcid.org/0000-0002-6217-1556 UNSPECIFIED Janka, Gritta UNSPECIFIED UNSPECIFIED UNSPECIFIED Wustrau, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Rakhmanov, Mirzokhid UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuchs, Ilka UNSPECIFIED UNSPECIFIED UNSPECIFIED Hennies, Hans C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ehl, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-212863
DOI:	10.1007/s10875-017-0443-1
Journal or Publication Title:	J. Clin. Immunol.
Volume:	37
Number:	8
Page Range:	S. 770 - 781
Date:	2017
Publisher:	SPRINGER/PLENUM PUBLISHERS
Place of Publication:	NEW YORK
ISSN:	1573-2592
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language STEM-CELL TRANSPLANTATION; PRIMARY IMMUNODEFICIENCIES; MUTATIONS; DIAGNOSIS; IDENTIFICATION; PATHOGENESIS; DEFICIENCY; BINDING; TYPE-3; UNC13D Multiple languages Immunology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21286