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Somatic mosaic mutation in TNFRSF1A as a cause of Tumor necrosis factor receptor-associated periodic syndrome- Impact on genetic counselling
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International audience. Introduction: Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is a rare monogenic systemic autoinflammatory disease caused mainly by germline heterozygous missense mutations in exons 2-4 of the TNF receptor super family member 1A (TNFRSF1A) gene. TRAPS is known as a familial disorder of autosomal dominant inheritance. Objective: To identify the genetic defect underlying the disease in a patient with a phenotype evocative of TRAPS. Methods: (i) The patient’s DNA was analyzed by Sanger sequencing of TNFRSF1A exons 2-4 followed by a NGS approach based on the targeted sequencing of the main genes involved in systemic autoinflammatory disorders; and (ii) Subpopulations of peripheral blood cells were subsequently analyzed in order to study the cellular distribution of the identified molecular defect.Results: (i) Clinical phenotype: A 36-year-old man presented since the age of 24 with recurrent episodes of fever (38-40C°) lasting for 1-2 weeks. The febrile attacks were accompanied with severe abdominal, thoracic and lower back pain, myalgia, and transitory erythematous eruptions localized at elbows and left lower limb. He also had an acute episode of pericarditis. No lymphadenopathy, ophthalmological or neurological symptoms were observed. Laboratory tests showed elevated inflammatory biological markers: increased serum levels of CRP (171 mg/l) with hyperleukocytosis (15000/l). Serum ferritin levels and kidney function tests were normal. (ii) Molecular bases: No heterozygous mutation was identified after Sanger sequencing of exons 2-4 of TNFRSF1A. The patient’s phenotype, highly evocative of TRAPS, prompted us to deepen the molecular investigations through the use of our autoinflammatory disorders NGS panel. We identified the c.176G>A p.(Cys59Tyr) TNFRSF1A mutation in a mosaic state with 14% of mutated allele in whole blood. This mutation (also known as C30Y) has already been reported, but in the heterozygous state, in three TRAPS families. We further studied the distribution of the mutated alleles in blood cells and observed a higher percentage of the mutated allele in myeloid cells (i.e. 15.8% in monocytes and 14.1% in neutrophils) than in lymphoid cells (i.e., 9.6% in T cells and 8.9% in B cells). Discussion: So far, only 3 other patients have been reported with a somatic mutation in TNFRSF1A. Among them, one displayed a germinal mosaicism. In our patient, the mosaicism predominantly involved the myeloid lineage (involved in the pathophysiology of TRAPS). In the 4 patients now identified with a TNFRSF1A somatic mosaic mutation, the phenotypic severity of TRAPS appears not to be related to the germinal/mosaic status of TNFRSF1A mutations.Conclusion: Somatic mosaic TNFRSF1A mutations should be sought in sporadic cases of TRAPS with no mutation identified by Sanger sequencing. Genetic counseling should take into account the fact that somatic mosaic mutations are not restricted to myeloid cells and may be present in other cell lineages.
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