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Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia

Lookup NU author(s): Dr Mario Abinun, Professor Andrew Cant, Professor Sophie HambletonORCiD, Dr Stephen Owens


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Clinical and genetic heterogeneity renders confirmation or exclusion of autoimmune lymphoproliferative syndrome difficult. To re-evaluate and improve the currently suggested diagnostic approach to patients with suspected FAS mutation, the most frequent cause of autoimmune lymphoproliferative syndrome, we prospectively determined 11 biomarkers in 163 patients with splenomegaly or lymphadenopathy and presumed or proven autoimmune cytopenia(s). Among 98 patients sequenced for FAS mutations in CD3(+)TCR alpha/CD4(-)CD8(-) "double negative" T cells, 32 had germline and six had somatic FAS mutations. The best a priori predictor of FAS mutations was the combination of vitamin B12 and soluble FAS ligand (cut-offs 1255 pg/mL and 559 pg/mL, respectively), which had a positive predictive value of 92% and a negative predictive value of 97%. We used these data to develop a web-based probability calculator for FAS mutations using the three most discriminatory biomarkers (vitamin B12, soluble FAS ligand, interleukin-10) of the 11 tested. Since more than 60% of patients with lymphoproliferation and autoimmune cytopenia(s) in our cohort did not harbor FAS mutations, 15% had somatic FAS mutations, and the predictive value of double-negative T-cell values was rather low (positive and negative predictive values of 61% and 77%, respectively), we argue that the previously suggested diagnostic algorithm based on determination of double-negative T cells and germline FAS sequencing, followed by biomarker analysis, is not efficient. We propose vitamin B12 and soluble FAS ligand assessment as the initial diagnostic step with subsequent decision on FAS sequencing supported by a probability-calculating tool.

Publication metadata

Author(s): Rensing-Ehl A, Janda A, Lorenz MR, Gladstone BP, Fuchs I, Abinun M, Albert M, Butler K, Cant A, Cseh AM, Ebinger M, Goldacker S, Hambleton S, Hebart H, Houet L, Kentouche K, Kuhnle I, Lehmberg K, Mejstrikova E, Niemeyer C, Minkov M, Neth O, Duckers G, Owens S, Rosler J, Schilling FH, Schuster V, Seidel MG, Smisek P, Sukova M, Svec P, Wiesel T, Gathmann B, Schwarz K, Vach W, Ehl S, Speckmann C

Publication type: Article

Publication status: Published

Journal: Haematologica

Year: 2013

Volume: 98

Issue: 12

Pages: 1948-1955

Print publication date: 12/07/2013

ISSN (print): 0390-6078

ISSN (electronic): 1592-8721

Publisher: Fondazione Ferrata Storti

DOI: 10.3324/haematol.2012.081901


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Funder referenceFunder name
European Society for Immunodeficiencies (ESID) by Baxter
01 GM 1111BBundesministerium fur Bildung und Forschung
BMBF 01 EO 0803Bundesministerium fur Bildung und Forschung