. 2024 Jan;153(1):203-215.

doi: 10.1016/j.jaci.2023.09.028. Epub 2023 Oct 2.

Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome

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

Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome

Olivier Pellé et al. J Allergy Clin Immunol. 2024 Jan.

. 2024 Jan;153(1):203-215.

doi: 10.1016/j.jaci.2023.09.028. Epub 2023 Oct 2.

Authors

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.

PubMed Disclaimer

Cited by

Autoimmune lymphoproliferative immunodeficiencies (ALPIDs): A proposed approach to redefining ALPS and other lymphoproliferative immune disorders.
Magerus A, Rensing-Ehl A, Rao VK, Teachey DT, Rieux-Laucat F, Ehl S. Magerus A, et al. J Allergy Clin Immunol. 2024 Jan;153(1):67-76. doi: 10.1016/j.jaci.2023.11.004. Epub 2023 Nov 17. J Allergy Clin Immunol. 2024. PMID: 37977527 Free PMC article. Review.
Inborn errors of immunity presenting with lymphoproliferation: lessons from a case series.
Costagliola G, De Marco E, Consonni F, Rocchi V, Legitimo A, Menconi M, Gambineri E, Casazza G, Consolini R. Costagliola G, et al. Ann Hematol. 2025 Jun;104(6):3117-3127. doi: 10.1007/s00277-025-06456-1. Epub 2025 Jun 24. Ann Hematol. 2025. PMID: 40553169 Free PMC article. Review.
Case Report: Clinical, molecular, and functional characterization of autoimmune lymphoproliferative syndrome-a family study with a multimodal diagnosis.
Guido BC, Camargo R, Silva CVDS, Dias ACS, de Pontes RM, Dos Santos Júnior ACM, Toscano RA, Tavares FS, Antunes AA, de Melo KM. Guido BC, et al. Front Pediatr. 2025 Jul 18;13:1639749. doi: 10.3389/fped.2025.1639749. eCollection 2025. Front Pediatr. 2025. PMID: 40755914 Free PMC article.
Genetic Testing in Patients with Autoimmune Lymphoproliferative Syndrome: Experience of 802 Patients at Cincinnati Children's Hospital Medical Center.
Xu X, Denton J, Wu Y, Liu J, Guan Q, Dawson DB, Bleesing J, Zhang W. Xu X, et al. J Clin Immunol. 2024 Jul 26;44(7):166. doi: 10.1007/s10875-024-01772-z. J Clin Immunol. 2024. PMID: 39060684 Free PMC article.
Beyond FAScinating: advances in diagnosis and management of autoimmune lymphoproliferative syndrome and activated PI3 kinase δ syndrome.
Rao VK, Pittaluga S, Uzel G. Rao VK, et al. Hematology Am Soc Hematol Educ Program. 2024 Dec 6;2024(1):126-136. doi: 10.1182/hematology.2024000537. Hematology Am Soc Hematol Educ Program. 2024. PMID: 39644063 Free PMC article. Review.

See all "Cited by" articles

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
Molecular Biology Databases
- GlyGen glycoinformatics resource
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome

Affiliations

Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome

Authors

Affiliations

Abstract

Similar articles

Cited by

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Research Materials

Miscellaneous

Abstract

Similar articles

Cited by

Publication types

MeSH terms

Substances

Related information

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Research Materials

Miscellaneous