Back to Search Start Over

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

Authors :
Rensing-Ehl A
Lorenz MR
Führer M
Willenbacher W
Willenbacher E
Sopper S
Abinun M
Maccari ME
König 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
Source :
The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2024 Jan; Vol. 153 (1), pp. 297-308.e12. Date of Electronic Publication: 2023 Nov 17.
Publication Year :
2024

Abstract

Background: Elevated TCRαβ <superscript>+</superscript> CD4 <superscript>-</superscript> CD8 <superscript>-</superscript> 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).<br />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.<br />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 <superscript>+</superscript> DNT, which can predict somatic loss of heterozygosity (sLOH).<br />Results: Nine of 16 patients with ALPS-U lacked FAS expression on CD57 <superscript>+</superscript> 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.<br />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.<br /> (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1097-6825
Volume :
153
Issue :
1
Database :
MEDLINE
Journal :
The Journal of allergy and clinical immunology
Publication Type :
Academic Journal
Accession number :
37979702
Full Text :
https://doi.org/10.1016/j.jaci.2023.11.006