A new case of Fas-associated death domain protein deficiency and update on treatment outcomes

Savic, Sinisa; Carter, Clive; Johnson, Colin A.; Logan, Clare V.; Morillo-Gutierrez, Beatriz; Thomas, J. Earl; Bacon, Chris M.; Cant, Andrew J.; Hambleton, Sophie

doi:10.1016/j.jaci.2015.02.002

Cited by 16 publications

(20 citation statements)

References 5 publications

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“…A flow chart of the process, from NGS to experimental validation, is crystallized in Table II and shown in Figure 2 for the example of human FADD deficiency, the first PID gene identified by WES (42). The initial discovery and the approach used are validated by the description of a novel case of FADD deficiency (43). …”

Section: Testing a Genetic Hypothesismentioning

confidence: 99%

Exome and genome sequencing for inborn errors of immunity

Meyts

Bosch

Bolze

et al. 2016

Journal of Allergy and Clinical Immunology

170

148

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The advent of next generation sequencing (NGS) in 2010 has transformed medicine and particularly the growing field of monogenic inborn errors of immunity, including primary immunodeficiencies (PID). NGS has facilitated the discovery of novel disease-causing genes and the genetic diagnosis of patients with PID. Whole-exome sequencing (WES) is presently the most cost-effective approach for PID research and diagnostics, though whole genome sequencing (WGS) offers several advantages. The scientific or diagnostic challenge consists in selecting one or two candidate variants among thousands of NGS calls. Variant- and gene-level computational methods as well as immunological hypotheses can help to narrow down this genome-wide search. The key to success is a well-informed genetic hypothesis on three key aspects: mode of inheritance, clinical penetrance, and genetic heterogeneity of the condition. This determines the search strategy and the frequency cut-offs for candidate alleles. Subsequent functional validation of the disease-causing effect of the candidate variant is critical. Even the most up-to-date dry lab cannot clinch this validation without a seasoned wet lab. The multifariousness of variations entails an experimental rigor even greater than traditional Sanger sequencing-based approaches, in order not to assign PID to false positives. Finding the needle in the haystack takes patience, prudence, and discernment.

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Section: Testing a Genetic Hypothesismentioning

confidence: 99%

Exome and genome sequencing for inborn errors of immunity

Meyts

Bosch

Bolze

et al. 2016

Journal of Allergy and Clinical Immunology

170

148

View full text Add to dashboard Cite

show abstract

“…They demonstrated a clinical phenotype mainly overlapping with ALPS-FAS, including decreased FAS-induced apoptosis, increased circulating DN T cells, elevated plasma FAS ligand, IL-10, and vitamin B12, variable degrees of lymphadenopathy or splenomegaly, but also recurrent febrile episodes with encephalopathy and seizures, cerebral atrophy, and structural cardiac abnormalities. Five patients carried a homozygous mutation affecting the same amino acid (p.C105W) [ 54 , 55 ] and one exhibited two compound heterozygous mutations (p.C105R and c.52-58delCACGAGC), one inherited from each parents [ 56 ].…”

Section: Non-fas Mutations In the Apoptosis Pathwaymentioning

confidence: 99%

The genetic landscape of the FAS pathway deficiencies

2021

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Dysfunction of the FAS-FASLG pathway causes a lymphoproliferative disorder with autoimmunity called Autoimmune lymphoproliferative syndrome (ALPS) mainly caused by FAS mutations. The goal of this review is to describe the genetic bases of the autoimmune lymphoproliferative syndrome and to underline their genetic complexity with the contribution of both germline and somatic events accounting for the variable clinical penetrance of the FAS mutations. Starting from the cohort of patients studied in the French cohort (>165 cases), we also reviewed the literature cases in order to depict a full description of the mutations affecting the FAS-FASLG pathway involved in the outcome of this rare non-malignant and non-infectious pediatric lymphoproliferative disease. We also discussed the variable clinical penetrance associated with mutations affecting the extracellular domain of the protein. Such non-penetrant germline mutations are frequently associated with an additional somatic event impacting the second allele of FAS . Moreover, the uncomplete clinical penetrance associated with mutations affecting the intracellular domain of FAS, in patient lacking additional FAS somatic event, suggested a potential digenic inheritance with a FAS mutation accompanied by a genetic modifier possibly impacting another player of the lymphocytes homeostasis (affecting the survival, activation or apoptosis of the peripheral leukocytes).

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“…Recurrent severe viral infections are thought to be mediated by FADD's role in TLR-independent innate immune responses and induction of IRF7 and IFN-α [2]. There are very few cases in the literature of FADD deficiency patients (4 patients from a consanguineous family in the original report [1] and 2 patients in a second report [3]). These patients seem to have worse outcomes than classical ALPS patients.…”

Section: To the Editormentioning

confidence: 99%

“…However, the natural history and optimal interventions for FADD deficiency patients remain to be determined, as so few prior patients have been described. Two previously described patients underwent hematopoietic stem cell transplantation (HSCT) [3]. The first patient experienced multiple post-transplant morbidities including cytopenias, enteropathies, and vasculopathy, while the second patient tolerated transplant with minimal morbidity [3].…”

Section: To the Editormentioning

confidence: 99%