Genetic profiling of autoinflammatory disorders in patients with periodic fever: a prospective study

Abstract

BackgroundPeriodic fever syndromes (PFS) are an emerging group of autoinflammatory disorders. Clinical overlap exists and multiple genetic analyses may be needed to assist diagnosis. We evaluated the diagnostic value of a 5-gene sequencing panel (5GP) in patients with undiagnosed PFS.MethodsSimultaneous double strand Sanger sequencing of MEFV, MVK, TNFRSF1A, NLRP3, NLRP12 genes was performed in 42 patients with unexplained PFS. Clinical features were correlated with genetic results.ResultsNone of 42 patients analyzed displayed a causative genotype. However, single or multiple genetic variants of uncertain significance were detected in 24 subjects. Only in 5 subjects a definite diagnosis was made by taking into account both genetic and clinical data (2 TRAPS syndrome; 2 FMF; 1 FCAS). Statistical analysis showed that patients carrying genetic variants in one or more of the five selected genes displayed a significantly lower response to glucocorticoids compared with subjects who had completely negative genetic results.ConclusionsThe sequencing of multiple genes is of little help in the diagnostics of PFS and can often lead to results of uncertain interpretation, thus the clinically driven sequencing of single genes should remain the recommended approach. However, the presence of single or multiple genetic variants of uncertain significance, even if not allowing any specific diagnosis, correlated with a poorer response to glucocorticoids, possibly indicating a multifactorial subgroup of PFS with differential response to pharmacological treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12969-015-0006-z) contains supplementary material, which is available to authorized users.

TNFRSF1A gene variant identified in a boy with recurrent episodes of fever

“…On the other hand, it is an exceedingly costly and somewhat time-consuming procedure, and this adds to the importance that all physicians, and especially pediatricians, be satisfactorily acquainted with the full range of clinical situations where it is rational to order such an analysis. This appears to be of the essence, since the usefulness of extensive genetic testing without proper clinical guidance is very doubtful, as highlighted, for instance, by the recently published experience in autoinflammatory disorders from a center in Trieste [21]. A deeper knowledge of possible genetic alterations and their complex consequences should ensure the necessary amount of critical thinking in determining whether testing is indicated or warranted, and this is, indeed, more than appropriate for the practice of medicine in the genomic age.…”

A variant allele of the Mediterranean‐fever gene increases the severity of gout

“…Mutated pyrin is able to activate NALP3 inflammasome without requiring stimulation by a ligand, which results in further aggravation of heightened inflammatory state when stimulated by a ligand (crystals) in gout. 15,33,34 It was previously reported that FMF-related MEFV gene variations, acting independently from the FMF clinical manifestation, may affect the phenotype of other inflammatory diseases by facilitating increased IL-1ß activation and inflammation. 35 Many studies have been conducted on the relationship between various diseases and FMF-related MEFV gene variation.…”

TRAPS, síndrome periódico asociado al receptor de necrosis tumoral: inmunopatogénesis y enfoque clínico

“…Desde el descubrimiento del gen responsable, TNFRS-F1A, en 1999, la fisiopatología ha sido ampliamente investigada; sin embargo, la patogénesis de TRAPS aún no está completamente entendida, ya que presenta mucha heterogeneidad clínica entre las diferentes mutaciones, así como entre los pacientes con la misma mutación (8).…”