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

Lookup NU author(s): Dr Mario Abinun

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Abstract

© 2023 American Academy of Allergy, Asthma & ImmunologyBackground: Elevated TCRαβ+CD4−CD8− double-negative T cells (DNT) and serum biomarkers help identify 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 on standard exon sequencing (ALPS-undetermined: ALPS-U). Objective: We sought 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 patients with ALPS-U 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 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 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.

Publication metadata

Author(s): Rensing-Ehl A, Lorenz MR, Fuhrer M, Willenbacher W, Willenbacher E, Sopper S, Abinun M, Maccari ME, Konig C, Haegele P, Fuchs S, Castro C, Kury P, Pelle O, Klemann C, Heeg M, Thalhammer J, Wegehaupt O, Fischer M, Goldacker S, Schulte B, Biskup S, Chatelain P, Schuster V, Warnatz K, Grimbacher B, Meinhardt A, Holzinger D, Oommen PT, Hinze T, Hebart H, Seeger K, Lehmberg K, Leahy TR, Claviez A, Vieth S, Schilling FH, Fuchs I, Gross M, Rieux-Laucat F, Magerus A, Speckmann C, Schwarz K, Ehl S

Publication type: Article

Publication status: Published

Journal: Journal of Allergy and Clinical Immunology

Year: 2024

Volume: 153

Issue: 1

Pages: 297-308.e12

Print publication date: 01/01/2024

Online publication date: 16/11/2023

Acceptance date: 09/11/2023

ISSN (print): 0091-6749

ISSN (electronic): 1097-6825

Publisher: Elsevier Inc.

URL: https://doi.org/10.1016/j.jaci.2023.11.006

DOI: 10.1016/j.jaci.2023.11.006

PubMed id: 37979702

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