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Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing

Item Type:Article
Title:Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing
Creators Name:Rensing-Ehl, A. and Lorenz, M.R. and Führer, M. and Willenbacher, W. and Willenbacher, E. and Sopper, S. and Abinun, M. and Maccari, M.E. and König, C. and Haegele, P. and Fuchs, S. and Castro, C. and Kury, P. and Pelle, O. and Klemann, C. and Heeg, M. and Thalhammer, J. and Wegehaupt, O. and Fischer, M. and Goldacker, S. and Schulte, B. and Biskup, S. and Chatelain, P. and Schuster, V. and Warnatz, K. and Grimbacher, B. and Meinhardt, A. and Holzinger, D. and Oommen, P.T. and Hinze, T. and Hebart, H. and Seeger, K. and Lehmberg, K. and Leahy, T.R. and Claviez, A. and Vieth, S. and Schilling, F.H. and Fuchs, I. and Groß, M. and Rieux-Laucat, F. and Magerus, A. and Speckmann, C. and Schwarz, K. and Ehl, S.
Abstract:BACKGROUND: Elevated TCRαβ(+)CD4(-)CD8(-) double-negative T-cells (DNT) and serum biomarkers help identifying FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified upon standard exon sequencing (ALPS-undetermined: ALPS-U). OBJECTIVE: We aimed to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway-related genes could explain these cases. METHODS: Genetic analysis included whole FAS gene sequencing, copy number variation analysis and sequencing of FAS cDNA and other FAS pathway related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss-of-heterozygosity (sLOH). RESULTS: Nine of 16 ALPS-U patients lacked FAS expression on CD57+DNT predicting heterozygous "loss of expression" FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7/9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT, one patient showed a FAS exon duplication. Three patients had reduced FAS expression, two of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the four ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH. CONCLUSION: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing. CLINICAL IMPLICATION: Detection of complex FAS pathway gene alterations by extended genetic analysis allows targeted therapy with sirolimus.
Keywords:ALPS, ALPS-U, FAS, FADD, Loss of Heterozygosity, Somatic Mutation, Promoter, Genetic Defect Accumulation, Double Negative T-Cells, DNT
Source:Journal of Allergy and Clinical Immunology
Page Range:297-308
Date:January 2024
Additional Information:Hedwig E. Deubzer is a member of the ALPS Study Group.
Official Publication:https://doi.org/10.1016/j.jaci.2023.11.006
PubMed:View item in PubMed

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