Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome

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

doi:10.1016/j.jaci.2023.09.028

Cited by 5 publications

(1 citation statement)

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“…The first clinical descriptions of ALPS emerged in the 60s, 2 while the molecular basis of ALPS was unveiled in 1995 by identifying mutations in FAS in patients with lymphocyte apoptosis defects 3 . Subsequently, mutations in FASLG , CASP10, FADD , and somatic mutations in FAS, all involved in the extrinsic apoptosis pathway, have broadened and complicated the genetic landscape of ALPS 4–6 . Meanwhile, the need to better delineate the ALPS phenotype has prompted the establishment of an ALPS classification based on the underlying pathogenic genetic variants.…”

Section: Introductionmentioning

confidence: 99%

Looking for ALPS: The value of a combined assessment of biochemical markers

Fernandez,

Touzot

2024

Pediatric Allergy Immunology

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BackgroundAutoimmune lymphoproliferative syndrome (ALPS) is a rare primary immune disorder caused by defect of the extrinsic apoptotic pathway. The current diagnostic criteria combine clinical features and typical biomarkers but have not been the object of clear international consensus.MethodsWe conducted a retrospective study on pediatric patients who were investigated for autoimmune cytopenia and/or lymphoproliferation at the CHU Sainte‐Justine Hospital over 10 years. Patients were screened using the combination of TCRαβ+ CD4− CD8− “double negative” (DN) T cells and soluble plasmatic FAS ligand (sFASL).ResultsAmong the 398 tested patients, the median sFASL and DN T cells were 200 ng/mL and 1.8% of TCRαβ+ T cells, respectively. sFASL was highly correlated with vitamin B12 levels. We identified five patients diagnosed with ALPS for whose sFASL and vitamin B12 levels were the more discriminating biomarkers. While ALPS diagnostic criteria had high sensibility, their predictive value remained low.ConclusionsFASL level can efficiently discriminate patients with ALPS when using the appropriate thresholds. Our study highlights the need for an international consensus to redefine the place and threshold of biological biomarkers for ALPS diagnosis.

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Section: Introductionmentioning

confidence: 99%

Looking for ALPS: The value of a combined assessment of biochemical markers

Fernandez,

Touzot

2024

Pediatric Allergy Immunology

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Genetic Approaches to Study Rheumatic Diseases and Its Implications in Clinical Practice

Rowczenio,

Aksentijevich

2024

Arthritis & Rheumatology

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Rare and complex rheumatic diseases (RDs) present with immense clinical variability inherent to all immunological diseases. In addition to systemic and organ‐specific inflammation, patients may display features of immunodeficiency or allergy, and as such, they may represent major diagnostic and therapeutic challenges. The person's genetic architecture has been a well‐established risk factor for RDs, albeit to variable degrees. Patients with early‐onset diseases and/or positive family history have a strong genetic component, while patients with late‐onset RDs demonstrate a more complex interplay of genetic and environmental risk factors. Overall, the genetic studies in RDs have been instrumental to our understanding of innate and adaptive immunity in human health and disease. The elucidation of the molecular causes underlying rare diseases has played a major role in the identification of genes that are critical in the regulation of inflammatory responses. In addition, studies of patients with rare disorders may help determine the mechanisms of more complex autoimmune diseases by identifying variants with small effect sizes in the same genes. In contrast, studies of common RDs are carried out in cohorts of patients with well‐established phenotypes and ancestry‐matched controls, and they aim to discover disease‐related pathways that can inform the development of novel targeted therapies. Knowing the genetic cause of a disease has helped patients and families understand the disease progression and outcome. Here, we discuss the current understanding of genetic heritability and challenges in the diagnosis of RDs and how this field may develop in the future.image

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Genetic Testing in Patients with Autoimmune Lymphoproliferative Syndrome: Experience of 802 Patients at Cincinnati Children’s Hospital Medical Center

Xu,

Denton,

et al. 2024

J Clin Immunol

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Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder featuring chronic lymphadenopathy, splenomegaly, cytopenias, and increased lymphoma risk. Differentiating ALPS from immunodeficiencies with overlapping symptoms is challenging. This study evaluated the performance and the diagnostic yield of a 15-gene NGS panel for ALPS at Cincinnati Children’s Hospital Medical Center. Samples from 802 patients submitted for ALPS NGS panel were studied between May 2014 and January 2023. A total of 62 patients (7.7%) had a definite diagnosis: 52/62 cases (84%) showed 37 unique pathogenic/likely pathogenic germline FAS variants supporting ALPS diagnosis (6.5%, 52/802). The ALPS diagnostic yield increased to 30% in patients who additionally fulfilled abnormal ALPS immunology findings criteria. 17/37 (46%) diagnostic FAS variants were novel variants reported for the first time in ALPS. 10/802 cases (1.2%) showed diagnostic findings in five genes (ADA2, CTLA4, KRAS, MAGT1, NRAS) which are related to autoimmune lymphoproliferative immunodeficiency (ALPID). Family studies enabled the reclassification of variants of unknown significance (VUS) and also the identification of at-risk family members of FAS-positive patients, which helped in the follow-up diagnosis and treatment. Alongside family studies, complete clinical phenotypes and abnormal ALPS immunology and Fas-mediated apoptosis results helped clarify uncertain genetic findings. This study describes the largest cohort of genetic testing for suspected ALPS in North America and highlights the effectiveness of the ALPS NGS panel in distinguishing ALPS from non-ALPS immunodeficiencies. More comprehensive assessment from exome or genome sequencing could be considered for undefined ALPS-U patients or non-ALPS immunodeficiencies after weighing cost, completeness, and timeliness of different genetic testing options.

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Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome

Cited by 5 publications

References 50 publications

Looking for ALPS: The value of a combined assessment of biochemical markers

Looking for ALPS: The value of a combined assessment of biochemical markers

Genetic Approaches to Study Rheumatic Diseases and Its Implications in Clinical Practice

Genetic Testing in Patients with Autoimmune Lymphoproliferative Syndrome: Experience of 802 Patients at Cincinnati Children’s Hospital Medical Center

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