Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome

Olivier Pellé; Solange Moreno; Myriam Ricarda Lorenz; Quentin Riller; Marita Fuehrer; Marie-Claude Stolzenberg; Maria Elena Maccari; Christelle Lenoir; Morgane Cheminant; Tanja Hinze; Holger F Hebart; Christoph König; Adrien Schvartz; Yohann Schmitt; Angélique Vinit; Emilie Henry; Aurore Touzart; Patrick Villarese; Pierre Isnard; Nathalie Neveux; Judith Landman-Parker; Capucine Picard; Fanny Fouyssac; Bénédicte Neven; Bodo Grimbacher; Carsten Speckmann; Alain Fischer; Sylvain Latour; Klaus Schwarz; Stephan Ehl; Frédéric Rieux-Laucat; Anne Rensing-Ehl; Aude Magérus

doi:10.1016/j.jaci.2023.09.028

Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome

J Allergy Clin Immunol. 2024 Jan;153(1):203-215. doi: 10.1016/j.jaci.2023.09.028. Epub 2023 Oct 2.

Authors

Olivier Pellé¹, Solange Moreno¹, Myriam Ricarda Lorenz², Quentin Riller¹, Marita Fuehrer³, Marie-Claude Stolzenberg¹, Maria Elena Maccari⁴, Christelle Lenoir⁵, Morgane Cheminant⁶, Tanja Hinze⁷, Holger F Hebart⁸, Christoph König⁹, Adrien Schvartz¹, Yohann Schmitt¹⁰, Angélique Vinit¹¹, Emilie Henry¹², Aurore Touzart¹³, Patrick Villarese¹³, Pierre Isnard¹⁴, Nathalie Neveux¹⁵, Judith Landman-Parker¹⁶, Capucine Picard¹⁷, Fanny Fouyssac¹⁸, Bénédicte Neven¹⁹, Bodo Grimbacher², Carsten Speckmann⁴, Alain Fischer²⁰, Sylvain Latour⁵, Klaus Schwarz²¹, Stephan Ehl², Frédéric Rieux-Laucat²², Anne Rensing-Ehl², Aude Magérus²³

Affiliations

¹ University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France.
² Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³ Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg-Hessen, Ulm, Germany; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁴ Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁵ University of Paris Cité, Paris, France; Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Imagine Institute, INSERM UMR 1163, Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France.
⁶ Clinical Hematology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; French National Reference Centre for Primary Immunodeficiencies (CEREDIH), Paris, France.
⁷ Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany.
⁸ Department of Internal Medicine, Kliniken Ostalb, Stauferklinikum, Mutlangen, Germany.
⁹ Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
¹⁰ University of Paris Cité, Paris, France; Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 and INSERM US24/CNRS UAR3633, Paris, France.
¹¹ Sorbonne Université, UMS037, PASS, Plateforme de Cytométrie de la Pitié-Salpêtrière CyPS, Paris, France.
¹² Genomics Platform, Translational Research Department, Research Center, Institut Curie, Paris Sciences et Lettres (PSL) Research University, Paris, France.
¹³ Laboratory of Onco-Hematology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Institut Necker-Enfants Malades (INEM), INSERM U1151, Paris, France.
¹⁴ Institut Necker-Enfants Malades (INEM), INSERM U1151, Paris, France; Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
¹⁵ Laboratory of Biological Nutrition, Faculty of Pharmacy, Paris University, Paris, France; Clinical Chemistry Department, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
¹⁶ Sorbonne Université, Assistance Publique-Hôpitaux de Paris (AP-HP) Armand Trousseau, Paris, France.
¹⁷ University of Paris Cité, Paris, France; Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Imagine Institute, INSERM UMR 1163, Paris, France; Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France.
¹⁸ Pediatric Oncology and Hematology Unit, Children Hospital, Vandoeuvre-les-Nancy, Paris, France.
¹⁹ University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Pediatric Immuno-hematology and Rheumatology Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France.
²⁰ University of Paris Cité, Paris, France; Pediatric Immuno-hematology and Rheumatology Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France; Collège de France, Paris, France.
²¹ Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg-Hessen, Ulm, Germany.
²² University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France. Electronic address: frederic.rieux-laucat@inserm.fr.
²³ University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France. Electronic address: aude.magerus@inserm.fr.

PMID: 37793571
DOI: 10.1016/j.jaci.2023.09.028

Abstract

Background: The autoimmune lymphoproliferative syndrome (ALPS) is a noninfectious and nonmalignant lymphoproliferative disease frequently associated with autoimmune cytopenia resulting from defective FAS signaling. We previously described germline monoallelic FAS (TNFRSF6) haploinsufficient mutations associated with somatic events, such as loss of heterozygosity on the second allele of FAS, as a cause of ALPS-FAS. These somatic events were identified by sequencing FAS in DNA from double-negative (DN) T cells, the pathognomonic T-cell subset in ALPS, in which the somatic events accumulated.

Objective: We sought to identify whether a somatic event affecting the FAS-associated death domain (FADD) gene could be related to the disease onset in 4 unrelated patients with ALPS carrying a germline monoallelic mutation of the FADD protein inherited from a healthy parent.

Methods: We sequenced FADD and performed array-based comparative genomic hybridization using DNA from sorted CD4⁺ or DN T cells.

Results: We found homozygous FADD mutations in the DN T cells from all 4 patients, which resulted from uniparental disomy. FADD deficiency caused by germline heterozygous FADD mutations associated with a somatic loss of heterozygosity was a phenocopy of ALPS-FAS without the more complex symptoms reported in patients with germline biallelic FADD mutations.

Conclusions: The association of germline and somatic events affecting the FADD gene is a new genetic cause of ALPS.

Keywords: ALPS; FADD; LOH; autoimmunity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / genetics
Autoimmune Diseases / genetics
Autoimmune Lymphoproliferative Syndrome* / genetics
Comparative Genomic Hybridization
DNA
Fas-Associated Death Domain Protein* / genetics
Fas-Associated Death Domain Protein* / metabolism
Germ Cells / pathology
Humans
Mutation
fas Receptor / genetics

Substances

DNA
FADD protein, human
fas Receptor
Fas-Associated Death Domain Protein